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  • 1.
    Abelein, Axel
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Abrahams, Jan Pieter
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Juri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. National Institute of Chemical Physics and Biophysics, Estonia.
    Luo, Jinghui
    Tiiman, Ann
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian K. T. S.
    The hairpin conformation of the amyloid beta peptide is an important structural motif along the aggregation pathway2014Ingår i: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 19, nr 4-5, s. 623-634Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The amyloid beta (A beta) peptides are 39-42 residue-long peptides found in the senile plaques in the brains of Alzheimer's disease (AD) patients. These peptides self-aggregate in aqueous solution, going from soluble and mainly unstructured monomers to insoluble ordered fibrils. The aggregation process(es) are strongly influenced by environmental conditions. Several lines of evidence indicate that the neurotoxic species are the intermediate oligomeric states appearing along the aggregation pathways. This minireview summarizes recent findings, mainly based on solution and solid-state NMR experiments and electron microscopy, which investigate the molecular structures and characteristics of the A beta peptides at different stages along the aggregation pathways. We conclude that a hairpin-like conformation constitutes a common motif for the A beta peptides in most of the described structures. There are certain variations in different hairpin conformations, for example regarding H-bonding partners, which could be one reason for the molecular heterogeneity observed in the aggregated systems. Interacting hairpins are the building blocks of the insoluble fibrils, again with variations in how hairpins are organized in the cross-section of the fibril, perpendicular to the fibril axis. The secondary structure propensities can be seen already in peptide monomers in solution. Unfortunately, detailed structural information about the intermediate oligomeric states is presently not available. In the review, special attention is given to metal ion interactions, particularly the binding constants and ligand structures of A beta complexes with Cu(II) and Zn(II), since these ions affect the aggregation process(es) and are considered to be involved in the molecular mechanisms underlying AD pathology.

  • 2.
    Abelein, Axel
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Bolognesi, Benedetta
    Dobson, Christopher M.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Lendel, Christofer
    Hydrophobicity and conformational change as mechanistic determinants for nonspecific modulators of amyloid β self-assembly2012Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 51, nr 1, s. 126-137Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The link between many neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, and the aberrant folding and aggregation of proteins has prompted a comprehensive search for small organic molecules that have the potential to inhibit such processes. Although many compounds have been reported to affect the formation of amyloid fibrils and/or other types of protein aggregates, the mechanisms by which they act are not well understood. A large number of compounds appear to act in a nonspecific way affecting several different amyloidogenic proteins. We describe here a detailed study of the mechanism of action of one representative compound, lacmoid, in the context of the inhibition of the aggregation of the amyloid β-peptide (Aβ) associated with Alzheimer's disease. We show that lacmoid binds Aβ(1-40) in a surfactant-like manner and counteracts the formation of all types of Aβ(1-40) and Aβ(1-42) aggregates. On the basis of these and previous findings, we are able to rationalize the molecular mechanisms of action of nonspecific modulators of protein self-assembly in terms of hydrophobic attraction and the conformational preferences of the polypeptide.

  • 3.
    Abelein, Axel
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The zinc ion – a minimal chaperone mimicking agent forretardation of amyloid β peptide fibril formationManuskript (preprint) (Övrigt vetenskapligt)
  • 4.
    Abelein, Axel
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Zinc as chaperone-mimicking agent for retardation of amyloid beta peptide fibril formation2015Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 17, s. 5407-5412Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Metal ions have emerged to play a key role in the aggregation process of amyloid beta (A beta) peptide that is closely related to the pathogenesis of Alzheimer's disease. A detailed understanding of the underlying mechanistic process of peptide-metal interactions, however, has been challenging to obtain. By applying a combination of NMR relaxation dispersion and fluorescence kinetics methods we have investigated quantitatively the thermodynamic A beta-Zn2+ binding features as well as how Zn2+ modulates the nucleation mechanism of the aggregation process. Our results show that, under near-physiological conditions, substoichiometric amounts of Zn2+ effectively retard the generation of amyloid fibrils. A global kinetic profile analysis reveals that in the absence of zinc A beta(40) aggregation is driven by a monomer-dependent secondary nucleation process in addition to fibril-end elongation. In the presence of Zn2+, the elongation rate is reduced, resulting in reduction of the aggregation rate, but not a complete inhibition of amyloid formation. We show that Zn2+ transiently binds to residues in the N terminus of the monomeric peptide. A thermodynamic analysis supports a model where the N terminus is folded around the Zn2+ ion, forming a marginally stable, short-lived folded A beta(40) species. This conformation is highly dynamic and only a few percent of the peptide molecules adopt this structure at any given time point. Our findings suggest that the folded A beta(40)-Zn2+ complex modulates the fibril ends, where elongation takes place, which efficiently retards fibril formation. In this conceptual framework we propose that zinc adopts the role of a minimal antiaggregation chaperone for A beta(40).

  • 5.
    Abelein, Axel
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. The National Institute of Chemical Physics and Biophysics, Estonia.
    Barth, Andreas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ionic Strength Modulation of the Free Energy Landscape of A beta(40) Peptide Fibril Formation2016Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 138, nr 21, s. 6893-6902Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Protein misfolding and formation of cross-beta structured amyloid fibrils are linked to, many neurodegenerative disorders. Although recently developed,quantitative approaches have started to reveal the molecular nature of self-assembly and fibril formation of proteins and peptides, it is yet unclear how these self-organization events are precisely modulated by microenvironmental factors, which are known to strongly affect the macroscopic aggregation properties. Here, we characterize the explicit effect of ionic strength on the microscopic aggregation rates of amyloid beta peptide (A beta 40) self-association, implicated in Alzheimer's disease. We found that physiological ionic strength accelerates A beta 40 aggregation kinetics by promoting surface-catalyzed secondary nucleation reactions. This promoted catalytic effect can be assigned to shielding of electrostatic repulsion between Monomers on the fibril surface or between the fibril surface itself and monomeric peptides. Furthermore, we observe the formation of two different beta-structured states with =similar but distinct spectroscopic features, which can be assigned to an off-pathway immature state (F-beta*) and a mature stable State (F-beta), where salt favors formation of the F-beta fibril morphology. Addition of salt to preformed F-beta* accelerates transition to F-beta, underlining the dynamic nature of A beta 40 fibrils in solution. On the basis of,these results we suggest a model where salt decreases the free-energy barrier for A beta 40 folding to the F-beta state, favoring the buildup of the mature fibril morphology while omitting competing, energetically less favorable structural states.

  • 6.
    Abelein, Axel
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kaspersen, Jørn Døvling
    Nielsen, Søren Bang
    Jensen, Grethe Vestergaard
    Christiansen, Gunna
    Pedersen, Jan Skov
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Otzen, Daniel E.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Formation of dynamic soluble surfactant-induced amyloid β peptide aggregation intermediates2013Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, nr 32, s. 23518-23528Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Intermediate amyloidogenic states along the amyloid β peptide (Aβ) aggregation pathway have been shown to be linked to neurotoxicity. To shed more light on the different structures that may arise during Aβ aggregation, we here investigate surfactant-induced Aβ aggregation. This process leads to co-aggregates featuring a β-structure motif that is characteristic for mature amyloid-like structures. Surfactants induce secondary structure in Aβ in a concentration-dependent manner, from predominantly random coil at low surfactant concentration, via β-structure to the fully formed α-helical state at high surfactant concentration. The β-rich state is the most aggregation-prone as monitored by thioflavin T fluorescence. Small angle x-ray scattering reveals initial globular structures of surfactant-Aβ co-aggregated oligomers and formation of elongated fibrils during a slow aggregation process. Alongside this slow (minutes to hours time scale) fibrillation process, much faster dynamic exchange (k(ex) ∼1100 s(-1)) takes place between free and co-aggregate-bound peptide. The two hydrophobic segments of the peptide are directly involved in the chemical exchange and interact with the hydrophobic part of the co-aggregates. Our findings suggest a model for surfactant-induced aggregation where free peptide and surfactant initially co-aggregate to dynamic globular oligomers and eventually form elongated fibrils. When interacting with β-structure promoting substances, such as surfactants, Aβ is kinetically driven toward an aggregation-prone state.

  • 7.
    Abelein, Axel
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Lang, Lisa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Lendel, Christofer
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Corrigendum to “Transient small molecule interactions kinetically modulate amyloid β peptide self-assembly” [FEBS Lett. 586 (2012) 3991–3995]2013Ingår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 587, nr 9, s. 1452-1452Artikel i tidskrift (Övrigt vetenskapligt)
  • 8.
    Abelein, Axel
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Lang, Lisa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Lendel, Christofer
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Transient small molecule interactions kinetically modulate amyloid beta peptide self-assembly2012Ingår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 586, nr 22, s. 3991-3995Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Small organic molecules, like Congo red and lacmoid, have been shown to modulate the self-assembly of the amyloid beta peptide (A beta). Here, we show that A beta forms NMR invisible non-toxic co-aggregates together with lacmoid as well as Congo red. We find that the interaction involves two distinct kinetic processes and at every given time point only a small fraction of A beta is in the co-aggregate. These weak transient interactions kinetically redirect the aggregation prone A beta from self-assembling into amyloid fibrils. These findings suggest that even such weak binders might be effective as therapeutics against pathogenic protein aggregation.

  • 9.
    Adrait, Annie
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Öhrström, Maria
    Barra, Anne-Laure
    The High Field Laboratory, CNRS/MPI, Grenoble, France.
    Thelander, Lars
    Department of Medical Biochemistry and Biophysicis, Umeå University.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    EPR studies on a stable sulfinyl radical observed in the iron-oxygen reconstituted Y177F/I263C protein double mutant of ribonucleotide reductase from mouse2002Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 41, nr 20, s. 6510-6516Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ribonucleotide reductase (RNR) catalyzes the biosynthesis of deoxyribonucleotides. The active enzyme contains a diiron center and a tyrosyl free radical required for enzyme activity. The radical is located at Y177 in the R2 protein of mouse RNR. The radical is formed concomitantly with the μ-oxo-bridged diferric center in a reconstitution reaction between ferrous iron and molecular oxygen in the protein. EPR at 9.6 and 285 GHz was used to investigate the reconstitution reaction in the double-mutant Y177F/I263C of mouse protein R2. The aim was to produce a protein-linked radical derived from the Cys residue in the mutant protein to investigate its formation and characteristics. The mutation Y177F hinders normal radical formation at Y177, and the I263C mutation places a Cys residue at the same distance from the iron center as Y177 in the native protein. In the reconstitution reaction, we observed small amounts of a transient radical with a probable assignment to a peroxy radical, followed by a stable sulfinyl radical, most likely located on C263. The unusual radical stability may be explained by the hydrophobic surroundings of C263, which resemble the hydrophobic pocket surrounding Y177 in native protein R2. The observation of a sulfinyl radical in RNR strengthens the relationship between RNR and another free radical enzyme, pyruvate formate-lyase, where a similar relatively stable sulfinyl radical has been observed in a mutant. Sulfinyl radicals may possibly be considered as stabilized forms of very short-lived thiyl radicals, proposed to be important intermediates in the radical chemistry of RNR.

  • 10. Akishiba, Misao
    et al.
    Takeuchi, Toshihide
    Kawaguchi, Yoshimasa
    Sakamoto, Kentarou
    Yu, Hao-Hsin
    Nakase, Ikuhiko
    Takatani-Nakase, Tomoka
    Madani, Fatemeh
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Futaki, Shiroh
    Cytosolic antibody delivery by lipid-sensitive endosomolytic peptide2017Ingår i: Nature Chemistry, ISSN 1755-4330, E-ISSN 1755-4349, Vol. 9, nr 8, s. 751-761Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    One of the major obstacles in intracellular targeting using antibodies is their limited release from endosomes into the cytosol. Here we report an approach to deliver proteins, which include antibodies, into cells by using endosomolytic peptides derived from the cationic and membrane-lytic spider venom peptide M-lycotoxin. The delivery peptides were developed by introducing one or two glutamic acid residues into the hydrophobic face. One peptide with the substitution of leucine by glutamic acid (L17E) was shown to enable a marked cytosolic liberation of antibodies (immunoglobulins G (IgGs)) from endosomes. The predominant membrane-perturbation mechanism of this peptide is the preferential disruption of negatively charged membranes (endosomal membranes) over neutral membranes (plasma membranes), and the endosomolytic peptide promotes the uptake by inducing macropinocytosis. The fidelity of this approach was confirmed through the intracellular delivery of a ribosome-inactivation protein (saporin), Cre recombinase and IgG delivery, which resulted in a specific labelling of the cytosolic proteins and subsequent suppression of the glucocorticoid receptor-mediated transcription. We also demonstrate the L17E-mediated cytosolic delivery of exosome-encapsulated proteins.

  • 11. Al Adwani, Salma
    et al.
    Padhi, Avinash
    Karadottir, Harpa
    Mörman, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Végvári, Ákos
    Johansson, Jan
    Rising, Anna
    Agerberth, Birgitta
    Bergman, Peter
    Citrullination Alters the Antibacterial and Anti-Inflammatory Functions of the Host Defense Peptide Canine Cathelicidin K9CATH In Vitro2021Ingår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 207, nr 3, s. 974-984Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    K9CATH is the sole cathelicidin in canines (dogs) and exhibits broad antimicrobial activity against both Gram-positive and Gram-negative bacteria. K9CATH also modulates inflammatory responses and binds to LPS. These activities depend on the secondary structure and a net-positive charge of the peptide. Peptidylarginine deiminases (PAD) convert cationic peptidyl arginine to neutral citrulline. Thus, we hypothesized that citrullination is a biologically relevant modification of the peptide that would reduce the antibacterial and LPS-binding activities of K9CATH. Recombinant PAD2 and PAD4 citrullinated K9CATH to various extents and circular dichroism spectroscopy revealed that both native and citrullinated K9CATH exhibited similar α-helical secondary structures. Notably, citrullination of K9CATH reduced its bactericidal activity, abolished its ability to permeabilize the membrane of Gram-negative bacteria and reduced the hemolytic capacity. Electron microscopy showed that citrullinated K9CATH did not cause any morphological changes of Gram-negative bacteria, whereas the native peptide caused clear alterations of membrane integrity, concordant with a rapid bactericidal effect. Finally, citrullination of K9CATH impaired its capacity to inhibit LPS-mediated release of proinflammatory molecules from mouse and canine macrophages. In conclusion, citrullination attenuates the antibacterial and the LPS-binding properties of K9CATH, demonstrating the importance of a net positive charge for antibacterial lysis of bacteria and LPS-binding effects and suggests that citrullination is a means to regulate cathelicidin activities.

  • 12. Al-Adwani, Salma
    et al.
    Wallin, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Balhuizen, Melanie D.
    Veldhuizen, Edwin J. A.
    Coorens, Maarten
    Landreh, Michael
    Végvári, Ákos
    Smith, Margaretha E.
    Qvarfordt, Ingemar
    Lindén, Anders
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Agerberth, Birgitta
    Bergman, Peter
    Studies on citrullinated LL-37: detection in human airways, antibacterial effects and biophysical properties2020Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 10, nr 1, artikel-id 2376Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Arginine residues of the antimicrobial peptide LL-37 can be citrullinated by peptidyl arginine deiminases, which reduce the positive charge of the peptide. Notably, citrullinated LL-37 has not yet been detected in human samples. In addition, functional and biophysical properties of citrullinated LL-37 are not fully explored. The aim of this study was to detect citrullinated LL-37 in human bronchoalveolar lavage (BAL) fluid and to determine antibacterial and biophysical properties of citrullinated LL-37. BAL fluid was obtained from healthy human volunteers after intra-bronchial exposure to lipopolysaccharide. Synthetic peptides were used for bacterial killing assays, transmission electron microscopy, isothermal titration calorimetry, mass-spectrometry and circular dichroism. Using targeted proteomics, we were able to detect both native and citrullinated LL-37 in BAL fluid. The citrullinated peptide did not kill Escherichia coli nor lysed human red blood cells. Both peptides had similar α-helical secondary structures but citrullinated LL-37 was more stable at higher temperatures, as shown by circular dichroism. In conclusion, citrullinated LL-37 is present in the human airways and citrullination impaired bacterial killing, indicating that a net positive charge is important for antibacterial and membrane lysing effects. It is possible that citrullination serves as a homeostatic regulator of AMP-function by alteration of key functions.

  • 13.
    Andersson, August
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mäler, Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    A kinetic model for peptide-induced leakage from vesicles and cells2007Konferensbidrag (Övrig (populärvetenskap, debatt, mm))
  • 14.
    Andersson, Charlotta S.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Öhrström, Maria
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Popović-Bijelić, Ana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Stenmark, Pål
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Högbom, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The manganese ion of the heterodinuclear Mn/Fe cofactor in Chlamydia trachomatis ribonucleotide reductase R2c is located at metal position 1.2012Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 134, nr 1, s. 123-125Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The essential catalytic radical of Class-I ribonucleotide reductase is generated and delivered by protein R2, carrying a dinuclear metal cofactor. A new R2 subclass, R2c, prototyped by the Chlamydia trachomatis protein was recently discovered. This protein carries an oxygen-activating heterodinuclear Mn(II)/Fe(II) metal cofactor and generates a radical-equivalent Mn(IV)/Fe(III) oxidation state of the metal site, as opposed to the tyrosyl radical generated by other R2 subclasses. The metal arrangement of the heterodinuclear cofactor remains unknown. Is the metal positioning specific, and if so, where is which ion located? Here we use X-ray crystallography with anomalous scattering to show that the metal arrangement of this cofactor is specific with the manganese ion occupying metal position 1. This is the position proximal to the tyrosyl radical site in other R2 proteins and consistent with the assumption that the high-valent Mn(IV) species functions as a direct substitute for the tyrosyl radical.

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  • 15.
    Assarsson, Maria
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Andersson, M E
    Högbom, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Persson, B O
    Sahlin, M
    Barra, A L
    Sjöberg, B M
    Nordlund, P
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Restoring proper radical generation by azide binding to the iron site of the E238A mutant R2 protein of ribonucleotide reductase from Escherichia coli.2001Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 276, nr 29, s. 26852-26859Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The enzyme activity of Escherichia coli ribonucleotide reductase requires the presence of a stable tyrosyl free radical and diiron center in its smaller R2 component. The iron/radical site is formed in a reconstitution reaction between ferrous iron and molecular oxygen in the protein. The reaction is known to proceed via a paramagnetic intermediate X, formally a Fe(III)-Fe(IV) state. We have used 9.6 GHz and 285 GHz EPR to investigate intermediates in the reconstitution reaction in the iron ligand mutant R2 E238A with or without azide, formate, or acetate present. Paramagnetic intermediates, i.e. a long-living X-like intermediate and a transient tyrosyl radical, were observed only with azide and under none of the other conditions. A crystal structure of the mutant protein R2 E238A/Y122F with a diferrous iron site complexed with azide was determined. Azide was found to be a bridging ligand and the absent Glu-238 ligand was compensated for by azide and an extra coordination from Glu-204. A general scheme for the reconstitution reaction is presented based on EPR and structure results. This indicates that tyrosyl radical generation requires a specific ligand coordination with 4-coordinate Fe1 and 6-coordinate Fe2 after oxygen binding to the diferrous site.

  • 16. Bacher, Felix
    et al.
    Doemoetoer, Orsolya
    Kaltenbrunner, Maria
    Mojovic, Milos
    Popovic-Bijelic, Ana
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ozarowski, Andrew
    Filipovic, Lana
    Radulovic, Sinisa
    Enyedy, Eva A.
    Arion, Vladimir B.
    Effects of Terminal Dimethylation and Metal Coordination of Proline-2-formylpyridine Thiosemicarbazone Hybrids on Lipophilicity, Antiproliferative Activity, and hR2 RNR Inhibition2014Ingår i: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 53, nr 23, s. 12595-12609Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The nickel(II), copper(II), and zinc(II) complexes of the proline-thiosemicarbazone hybrids 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone (l-Pro-FTSC or (S)-H2L1) and 3-methyl-(R)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone (d-Pro-FTSC or (R)-H2L1), as well as 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine 4,4-dimethyl-thiosemicarbazone (dm-l-Pro-FTSC or (S)-H2L2), namely, [Ni(l-Pro-FTSC-2H)](2) (1), [Ni(d-Pro-FTSC-2H)](2) (2), [Ni(dm-l-Pro-FTSC-2H)](2) (3), [Cu(dm-l-Pro-FTSC-2H)] (6), [Zn(l-Pro-FTSC-2H)] (7), and [Zn(d-Pro-FTSC-2H)] (8), in addition to two previously reported, [Cu(l-Pro-FTSC-2H)] (4), [Cu(d-Pro-FTSC-2H)] (5), were synthesized and characterized by elemental analysis, one- and two-dimensional (1)H and (13)C NMR spectroscopy, circular dichroism, UV-vis, and electrospray ionization mass spectrometry. Compounds 1-3, 6, and 7 were also studied by single-crystal X-ray diffraction. Magnetic properties and solid-state high-field electron paramagnetic resonance spectra of 2 over the range of 50-420 GHz were investigated. The complex formation processes of l-Pro-FTSC with nickel(II) and zinc(II) were studied in aqueous solution due to the excellent water solubility of the complexes via pH potentiometry, UV-vis, and (1)H NMR spectroscopy. The results of the antiproliferative activity in vitro showed that dimethylation improves the cytotoxicity and hR2 RNR inhibition. Therefore, introduction of more lipophilic groups into thiosemicarbazone-proline backbone becomes an option for the synthesis of more efficient cytotoxic agents of this family of compounds.

  • 17.
    Berntsson, Elina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Tallinn University of Technology, Estonia.
    Paul, Suman
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Vosough, Faraz
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Sholts, Sabrina B.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. The National Institute of Chemical Physics and Biophysics, Estonia.
    Roos, Per M.
    Barth, Andreas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Lithium ions display weak interaction with amyloid-beta (Aβ) peptides and have minor effects on their aggregation2021Ingår i: Acta Biochimica Polonica, ISSN 0001-527X, E-ISSN 1734-154X, Vol. 68, nr 2, s. 169-179Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alzheimer’s disease (AD) is an incurable disease and the main cause of age-related dementia worldwide, despite decades of research. Treatment of AD with lithium (Li) has shown promising results, but the underlying mechanism is unclear. The pathological hallmark of AD brains is deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils. The plaques contain also metal ions of e.g. Cu, Fe, and Zn, and such ions are known to interact with Aβ peptides and modulate their aggregation and toxicity. The interactions between Aβ peptides and Li+ions have however not been well investigated. Here, we use a range of biophysical techniques to characterize in vitro interactions between Aβ peptides and Li+ions. We show that Li+ions display weak and non-specific interactions with Aβ peptides, and have minor effects on Aβ aggregation. These results indicate that possible beneficial effects of Li on AD pathology are not likely caused by direct interactions between Aβ peptides and Li+ions.

  • 18.
    Berntsson, Elina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Tallinn University of Technology, Estonia.
    Sardis, Merlin
    Noormägi, Andra
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. The National Institute of Chemical Physics and Biophysics, Estonia.
    Roos, Per M.
    Töugu, Vello
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Palumaa, Peep
    Wärmländer, Sebastian K.T.S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mercury Ion Binding to Apolipoprotein E Variants ApoE2, ApoE3, and ApoE4: Similar Binding Affinities but Different Structure Induction Effects2022Ingår i: ACS Omega, E-ISSN 2470-1343, Vol. 7, nr 33, s. 28924-28931Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mercury intoxication typically produces more severe outcomes in people with the APOE-ε4 gene, which codes for the ApoE4 variant of apolipoprotein E, compared to individuals with the APOE-ε2 and APOE-ε3 genes. Why the APOE-ε4 allele is a risk factor in mercury exposure remains unknown. One proposed possibility is that the ApoE protein could be involved in clearing of heavy metals, where the ApoE4 protein might perform this task worse than the ApoE2 and ApoE3 variants. Here, we used fluorescence and circular dichroism spectroscopies to characterize the in vitro interactions of the three different ApoE variants with Hg(I) and Hg(II) ions. Hg(I) ions displayed weak binding to all ApoE variants and induced virtually no structural changes. Thus, Hg(I) ions appear to have no biologically relevant interactions with the ApoE protein. Hg(II) ions displayed stronger and very similar binding affinities for all three ApoE isoforms, with KD values of 4.6 μM for ApoE2, 4.9 μM for ApoE3, and 4.3 μM for ApoE4. Binding of Hg(II) ions also induced changes in ApoE superhelicity, that is, altered coil–coil interactions, which might modify the protein function. As these structural changes were most pronounced in the ApoE4 protein, they could be related to the APOE-ε4 gene being a risk factor in mercury toxicity.

  • 19.
    Berntsson, Elina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Vosough, Faraz
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Noormagi, Andra
    Padari, Kärt
    Asplund, Fanny
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gielnik, Maciej
    Paul, Suman
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Tõugu, Vello
    Roos, Per M.
    Kozak, Maciej
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. CellPept Sweden AB, Sweden.
    Barth, Andreas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Pooga, Margus
    Palumaa, Peep
    Wärmländer, Sebastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. CellPept Sweden AB, Sweden.
    Characterization of Uranyl (UO22+) Ion Binding to Amyloid Beta (Aβ) Peptides: Effects on Aβ Structure and Aggregation2023Ingår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 14, nr 15, s. 2618-2633Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Uranium (U) is naturally present in ambient air, water, and soil, and depleted uranium (DU) is released into the environment via industrial and military activities. While the radiological damage from U is rather well understood, less is known about the chemical damage mechanisms, which dominate in DU. Heavy metal exposure is associated with numerous health conditions, including Alzheimer’s disease (AD), the most prevalent age-related cause of dementia. The pathological hallmark of AD is the deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils in the brain. However, the toxic species in AD are likely oligomeric Aβ aggregates. Exposure to heavy metals such as Cd, Hg, Mn, and Pb is known to increase Aβ production, and these metals bind to Aβ peptides and modulate their aggregation. The possible effects of U in AD pathology have been sparsely studied. Here, we use biophysical techniques to study in vitro interactions between Aβ peptides and uranyl ions, UO22+, of DU. We show for the first time that uranyl ions bind to Aβ peptides with affinities in the micromolar range, induce structural changes in Aβ monomers and oligomers, and inhibit Aβ fibrillization. This suggests a possible link between AD and U exposure, which could be further explored by cell, animal, and epidemiological studies. General toxic mechanisms of uranyl ions could be modulation of protein folding, misfolding, and aggregation. 

  • 20.
    Berntsson, Elina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Tallinn University of Technology, Estonia.
    Vosough, Faraz
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Svantesson, Teodor
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Pansieri, Jonathan
    Iashchishyn, Igor A.
    Ostojic, Lucija
    Dong, Xiaolin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Paul, Suman
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Tallinn University of Technology, Estonia.
    Roos, Per M.
    Barth, Andreas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Morozova-Roche, Ludmilla A.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Humanistiska fakulteten, Institutionen för arkeologi och antikens kultur.
    Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aβ) peptides2023Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 13, nr 1, artikel-id 3341Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alzheimer's disease (AD) is the most common cause of dementia worldwide. AD brains display deposits of insoluble amyloid plaques consisting mainly of aggregated amyloid-beta (A beta) peptides, and A beta oligomers are likely a toxic species in AD pathology. AD patients display altered metal homeostasis, and AD plaques show elevated concentrations of metals such as Cu, Fe, and Zn. Yet, the metal chemistry in AD pathology remains unclear. Ni(II) ions are known to interact with A beta peptides, but the nature and effects of such interactions are unknown. Here, we use numerous biophysical methods-mainly spectroscopy and imaging techniques-to characterize A beta/Ni(II) interactions in vitro, for different A beta variants: A beta(1-40), A beta(1-40)(H6A, H13A, H14A), A beta(4-40), and A beta(1-42). We show for the first time that Ni(II) ions display specific binding to the N-terminal segment of full-length A beta monomers. Equimolar amounts of Ni(II) ions retard A beta aggregation and direct it towards non-structured aggregates. The His6, His13, and His14 residues are implicated as binding ligands, and the Ni(II)center dot A beta binding affinity is in the low mu M range. The redox-active Ni(II) ions induce formation of dityrosine cross-links via redox chemistry, thereby creating covalent A beta dimers. In aqueous buffer Ni(II) ions promote formation of beta sheet structure in A beta monomers, while in a membrane-mimicking environment (SDS micelles) coil-coil helix interactions appear to be induced. For SDS-stabilized A beta oligomers, Ni(II) ions direct the oligomers towards larger sizes and more diverse (heterogeneous) populations. All of these structural rearrangements may be relevant for the A beta aggregation processes that are involved in AD brain pathology.

  • 21. Biswas, Abhijit
    et al.
    Maloverjan, Maria
    Padari, Kärt
    Abroi, Aare
    Rätsep, Margus
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. CellPept Sweden AB, Sweden.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. CellPept Sweden AB, Sweden.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. CellPept Sweden AB, Sweden.
    Kisand, Vambola
    Löhmus, Rünno
    Pooga, Margus
    Choosing an Optimal Solvent Is Crucial for Obtaining Cell-Penetrating Peptide Nanoparticles with Desired Properties and High Activity in Nucleic Acid Delivery2023Ingår i: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 15, nr 2, artikel-id 396Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cell-penetrating peptides (CPPs) are highly promising transfection agents that can deliver various compounds into living cells, including nucleic acids (NAs). Positively charged CPPs can form non-covalent complexes with negatively charged NAs, enabling simple and time-efficient nanoparticle preparation. However, as CPPs have substantially different chemical and physical properties, their complexation with the cargo and characteristics of the resulting nanoparticles largely depends on the properties of the surrounding environment, i.e., solution. Here, we show that the solvent used for the initial dissolving of a CPP determines the properties of the resulting CPP particles formed in an aqueous solution, including the activity and toxicity of the CPP–NA complexes. Using different biophysical methods such as dynamic light scattering (DLS), atomic force microscopy (AFM), transmission and scanning electron microscopy (TEM and SEM), we show that PepFect14 (PF14), a cationic amphipathic CPP, forms spherical particles of uniform size when dissolved in organic solvents, such as ethanol and DMSO. Water-dissolved PF14, however, tends to form micelles and non-uniform aggregates. When dissolved in organic solvents, PF14 retains its α-helical conformation and biological activity in cell culture conditions without any increase in cytotoxicity. Altogether, our results indicate that by using a solvent that matches the chemical nature of the CPP, the properties of the peptide–cargo particles can be tuned in the desired way. This can be of critical importance for in vivo applications, where CPP particles that are too large, non-uniform, or prone to aggregation may induce severe consequences.

  • 22. Björklund, Jörgen
    et al.
    Biverståhl, Henrik
    Gräslund, Astrid
    Mäler, Lena
    Brzezinski, Peter
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Real-time transmembrane translocation of penetratin driven by light-generated proton pumping.2006Ingår i: Biophys J, ISSN 0006-3495, Vol. 91, nr 4, s. L29-31Artikel i tidskrift (Refereegranskat)
  • 23.
    Björnerås, Johannes
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mäler, Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Membrane Interaction of Disease-Related Dynorphin A Variants2013Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 52, nr 24, s. 4157-4167Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The membrane interaction properties of two single-residue variants, R6W and L5S, of the 17-amino acid neuropeptide dynorphin A (DynA) were studied by circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy. Corresponding gene mutations have recently been discovered in humans and causatively linked to a neurodegenerative disorder. The peptides were investigated in buffer and in isotropic solutions of q = 0.3 bicelles with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or DMPC (0.8) and 1,2-dimyristoyl-sn-glycero-3-phospho(1'-rac-glycerol) (DMPG) (0.2). The CD results and the NMR secondary chemical shifts show that R6W-DynA has a small a-helical fraction in buffer, which increases in the presence of bicelles, while L5S-DynA is mainly unstructured under all conditions studied here. R6W-DynA has an almost complete association with zwitterionic bicelles (similar to 90%, as probed by NMR diffusion experiments), similar to the behavior of wtDynA, while L5S-DynA has a weaker association (similar to 50%). For all peptides, the level of bicelle association is increased in negatively charged bicelles. The L5A-DynA peptide adopts a very shallow position in the headgroup region of the bicelle bilayer, as studied by paramagnetic spin relaxation enhancement experiments using paramagnetic probes. Similarly, the results show that R6W-DynA is more deeply buried in the bilayer, with only the C-terminal residues exposed to solvent, again more similar to the case of wild-type DynA. We suggest that the results presented here may explain the differences in cell toxicity of these disease-related neuropeptide variants.

  • 24.
    Björnerås, Johannes
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mäler, Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The membrane interaction of dynorphin A depends on lipid head-group chargeManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The influence of lipid bicelles on the dynamics of the opioid peptide DynA has been investigated by Nuclear Magnetic Resonance. DynA exerts its opioid effects mainly through interactions with the κ subtype of the opioid receptors, but has also been demonstrated to have direct interactions with membranes. Among other properties, it has been shown that the peptide causes membrane disruption and may penetrate bilayers. Despite the fact that DynA appears to bind tightly to model lipid bilayers, no structure induction has been observed. To further study the effect of membrane interactions we have here therefore measured the fast local dynamics of DynA specifically labeled with 15N in three backbone amide sites (Gly2, Leu5 and Leu12) in fast-tumbling bicelles, both with and without the incorporation of the negatively charged dimyristoylglycerol. We also examined the amide exchange in the two bicelles. We find that despite the fact that DynA is largely unstructured in both types of bicelles, the peptide has restricted backbone dynamics, which depends on the presence of negatively charged lipids. Moreover we see that the lipid dependence is not uniform throughout the sequence, but is most noticeable for Leu5, which precedes an unusually basic stretch of amino acid residues. The findings indicate that this basic sequence may be of significance for bilayer recognition. Finally, we note that the dynamical behavior of the peptide is much more influenced by the lipid surroundings than what the structural properties are.

  • 25.
    Björnerås, Johannes
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kurnik, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Oliveberg, Mikael
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mäler, Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Direct detection of neuropeptide dynorphin A binding to the second extracellular loop of the kappa opioid receptor using a soluble protein scaffold2014Ingår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 281, nr 3, s. 814-824Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The molecular determinants for selectivity of ligand binding to membrane receptors are of key importance for the understanding of cellular signalling, as well as for rational therapeutic intervention. In the present study, we target the interaction between the kappa opioid receptor (KOR) and its native peptide ligand dynorphin A (DynA) using solution state NMR spectroscopy, which is generally made difficult by the sheer size of membrane bound receptors. Our method is based on 'transplantation' of an extracellular loop of KOR into a 'surrogate' scaffold; in this case, a soluble beta-barrel. Our results corroborate the general feasibility of the method, showing that the inserted receptor segment has negligible effects on the properties of the scaffold protein, at the same time as maintaining an ability to bind its native DynA ligand. Upon DynA binding, only small induced chemical shift changes of the KOR loop were observed, whereas chemical shift changes of DynA and NMR paramagnetic relaxation data show conclusively that the peptide interacts with the inserted loop. The binding interface is composed of a disordered part of the KOR loop and involves both electrostatic and hydrophobic interactions. Even so, simultaneous effects along the DynA sequence upon binding show that control of the recognition is a concerted event.

  • 26.
    Bárány-Wallje, Elsa
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Andersson, August
    Gräslund, Astrid
    Mäler, Lena
    Dynamics of transportan in bicelles is surface charge dependent.2006Ingår i: J Biomol NMR, ISSN 0925-2738, Vol. 35, nr 2, s. 137-47Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this study we investigated the dynamic behavior of the chimeric cell-penetrating peptide transportan in membrane-like environments using NMR. Backbone amide 15N spin relaxation was used to investigate the dynamics in two bicelles: neutral DMPC bicelles and partly negatively charged DMPG-containing bicelles.

    The structure of the peptide as judged from CD and chemical shifts is similar in the two cases. Both the overall motion as well as the local dynamics is, however, different in the two types of bicelles. The overall dynamics of the peptide is significantly slower in the partly negatively charged bicelle environment, as evidenced by longer global correlation times for all measured sites.

    The local motion, as judged from generalized order parameters, is for all sites in the peptide more restricted when bound to negatively charged bicelles than when bound to neutral bicelles (increase in S2 is on average 0.11±0.07). The slower dynamics of transportan in charged membrane model systems cause significant line broadening in the proton NMR spectrum, which in certain cases limits the observation of 1H signals for transportan when bound to the membrane. The effect of transportan on DMPC and DHPC motion in zwitterionic bicelles was also investigated, and the motion of both components in the bicelle was found to be affected.

  • 27.
    Bárány-Wallje, Elsa
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. biofysik.
    Andersson, August
    Gräslund, Astrid
    Mäler, Lena
    NMR solution structure and position of transportan in neutral phospholipid bicelles.2004Ingår i: FEBS Lett, ISSN 0014-5793, Vol. 567, nr 2-3, s. 265-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Transportan is a chimeric cell-penetrating peptide constructed from the peptides galanin and mastoparan, which has the ability to internalize living cells carrying a hydrophilic load. In this study, we have determined the NMR solution structure and investigated the position of transportan in neutral bicelles. The structure revealed a well-defined -helix in the C-terminal mastoparan part of the peptide and a weaker tendency to form an -helix in the N-terminal domain. The position of the peptide in relation to the membrane, as studied by adding paramagnetic probes, shows that the peptide lies parallel to, and in the head-group region of the membrane surface. This result is supported by amide proton secondary chemical shifts.

  • 28.
    Bárány-Wallje, Elsa
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gaur, Jugnu
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Lundberg, Pontus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Langel, Ülo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Differential membrane perturbation caused by the cell penetrating peptide Tp10 depending on attached cargo2007Ingår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 581, nr 13, s. 2389-2393Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The membrane leakage caused by the cell penetrating peptide Tp10, a variant of transportan, was studied in large unilamellar vesicles with the entrapped fluorophore calcein. The vesicles were composed of zwitterionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine. A significant decrease in membrane leakage was found when the 55 kDa streptavidin protein was attached to Tp10. When a 5.4 kDa peptide nucleic acid molecule was attached, the membrane leakage was comparable to that caused by Tp10 alone. The results suggest that direct membrane effects may cause membrane translocation of Tp10 alone and of smaller complexes, whereas these effects do not contribute for larger cargoes.

  • 29.
    Bárány-Wallje, Elsa
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mäler, Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Structure and dynamics of galanin in phospholipid bicelles2007Konferensbidrag (Övrig (populärvetenskap, debatt, mm))
  • 30. Chemerovski-Glikman, Marina
    et al.
    Rozentur-Shkop, Eva
    Richman, Michal
    Grupi, Asaf
    Getler, Asaf
    Cohen, Haim Y.
    Shaked, Hadassa
    Wallin, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Haas, Elisha
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Chill, Jordan H.
    Rahimipour, Shai
    Self-Assembled Cyclic D,L-alpha-Peptides as Generic Conformational Inhibitors of the alpha-Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies2016Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, nr 40, s. 14236-14246Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Many peptides and proteins with large sequences and structural differences self-assemble into disease-causing amyloids that share very similar biochemical and biophysical characteristics, which may contribute to their cross-interaction. Here, we demonstrate how the self-assembled, cyclic D,L-alpha-peptide CP-2, which has similar structural and functional properties to those of amyloids, acts as a generic inhibitor of the Parkinson's disease associated alpha-synuclein (alpha-syn) aggregation to toxic oligomers by an, off-pathway mechanism. We show that CP-2 interacts with the N-terminal and the non-amyloid-beta component region of alpha-syn, which are responsible for alpha-syn's membrane intercalation and self-assembly, thus changing the overall conformation of alpha-syn. CP-2 also remodels alpha-syn fibrils to nontoxic amorphous species and permeates cells through endosomes/lysosomes to reduce the accumulation and toxicity of intracellular alpha-syn in neuronal cells overexpressing alpha-syn. Our studies suggest that targeting the common structural conformation of amyloids may be a promising approach for developing new therapeutics for amyloidogenic diseases.

  • 31.
    Danielsson, J
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Andersson, A
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, J
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, A
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    15N relaxation study of the amyloid beta-peptide structural propensities and persistence length.2006Ingår i: Magn Reson Chem, ISSN 0749-1581, Vol. 44, nr S1, s. S114-21Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The dynamics of monomeric Alzheimer A(1-40) in aqueous solution was studied using heteronuclear NMR experiments. 15N NMR relaxation rates of amide groups report on the dynamics in the peptide chain and make it possible to estimate structural propensities from temperature-dependent relaxation data and chemical shifts change analysis. The persistence length of the polypeptide chain was determined using a model in which the influence of neighboring residue relaxation is assumed to decay exponentially as a function of distance. The persistence length of the A(1-40) monomer was found to decrease from eight to three residues when temperature was increased from 3 to 18 °C. At 3 °C the peptide shows structural propensities that correlate well with the suggested secondary structure regions of the peptide to be present in the fibrils, and with the -helical structure in membrane-mimicking systems. Our data leads to a structural model for the monomeric soluble -peptide with six different regions of secondary structure propensities. The peptide has two regions with -strand propensity (residues 16-24 and 31-40), two regions with high PII-helix propensity (residues 1-4 and 11-15) and two unstructured regions with higher mobility (residues 5-10 and 25-30) connecting the structural elements. Copyright © 2006 John Wiley & Sons, Ltd.

  • 32.
    Danielsson, Jens
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Pierattelli, Roberta
    Banci, Lucia
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    High-resolution NMR studies of the sinc-binding site of the Alzheimer’s Aβ-peptide2007Ingår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 274, nr 1, s. 46-59Artikel i tidskrift (Refereegranskat)
  • 33.
    Davydov, Albert
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Öhrström, Maria
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Liu, Aimin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Thelander, Lars
    Department of Medical Biosciences, Medical Biochemistry, Umeå Universtity.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Chemical reduction of the diferric/radical center in protein R2 from mouse ribonucleotide reductase is independent of the proposed radical transfer pathway2002Ingår i: Inorganica Chimica Acta, ISSN 0020-1693, E-ISSN 1873-3255, Vol. 331, nr 1, s. 65-72Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The rates of reduction of the diferric/radical center in mouse ribonucleotide reductase protein R2 were studied by light absorption and EPR in the native protein and in three point mutants of conserved residues involved in the proposed radical transfer pathway (D266A, W103Y) or in the unstructured C terminal domain (Y370W). The pseudo-first order rate constants for chemical reduction of the tyrosyl radical and diferric center by hydroxyurea, sodium dithionite or the dihydro form of flavin adenine dinucleotide, were comparable with or higher (particularly D266A, by dithionite) than in native R2. Molecular modeling of the D266A mutant showed that the iron/radical site should be more accessible for external reductants in the mutant than in native R2. The results indicate that no specific pathway is required for the reduction. The dihydro form of flavin adenine dinucleotide was found to be a very efficient reductant in the studied proteins compared to dithionite alone. The EPR spectra of the mixed-valent Fe(II)Fe(III) sites formed by chemical reduction in the D266A and W103Y mutants were clearly different from the spectrum observed in the native protein, indicating that the structure of the diferric site was affected by the mutations, as also suggested by the modeling study. No difference was observed between the mixed-valent EPR spectra generated by chemical reduction in Y370W mutant and native mouse R2 protein

  • 34. Dobrov, Anatolie
    et al.
    Goeschl, Simone
    Jakupec, Michael A.
    Popovic-Bijelic, Ana
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Rapta, Peter
    Arion, Vladimir B.
    A highly cytotoxic modified paullone ligand bearing a TEMPO free-radical unit and its copper(II) complex as potential hR2 RNR inhibitors2013Ingår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 49, nr 85, s. 10007-10009Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A new paullone-TEMPO conjugate and its copper(II) complex inhibit RNR activity and show high antiproliferative activity in human cancer cell lines.

  • 35. Dong, Xiaolin
    et al.
    Svantesson, Teodor
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Sholts, Sabrina B.
    Wallin, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. The National Institute of Chemical Physics and Biophysics, Estonia.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Copper ions induce dityrosine-linked dimers in human but not in murine islet amyloid polypeptide (IAPP/amylin)2019Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 510, nr 4, s. 520-524Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Dysregulation and aggregation of the peptide hormone IAPP (islet amyloid polypeptide, a.k.a. amylin) into soluble oligomers that appear to be cell-toxic is a known aspect of diabetes mellitus (DM) Type 2 pathology. IAPP aggregation is influenced by several factors including interactions with metal ions such as Cu(II). Because Cu(II) ions are redox-active they may contribute to metal-catalyzed formation of oxidative tyrosyl radicals, which can generate dityrosine cross-links. Here, we show that such a process, which involves Cu(II) ions bound to the IAPP peptide together with H2O2, can induce formation of large amounts of IAPP dimers connected by covalent dityrosine cross-links. This cross-linking is less pronounced at low pH and for murine IAPP, likely due to less efficient Cu(II) binding. Whether IAPP can carry out its hormonal function as a cross-linked dimer is unknown. As dityrosine concentrations are higher in blood plasma of DM Type 2 patients - arguably due to disease-related oxidative stress - and as dimer formation is the first step in protein aggregation, generation of dityrosine-linked dimers may be an important factor in IAPP aggregation and thus relevant for DM Type 2 progression.

  • 36. Esbjörner, Elin K.
    et al.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Nordén, Bengt
    Membrane Interactions of Cell-Penetrating Peptides2007Ingår i: Handbook of Cell-Penetrating Peptides / [ed] Ülo Langel, Boca Raton: CRC Press, 2007, 2, s. 109-137Kapitel i bok, del av antologi (Refereegranskat)
  • 37.
    Esbjörner, Elin K.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Oglęcka, Kamila
    Lincoln, Per
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Nordén, Bengt
    Membrane binding of pH-sensitive Influenza fusion peptides. Positioning, configuration and induced leakage in lipid vesicles models2007Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 46, nr 47, s. 13490-13504Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    pH-sensitive HA2 fusion peptides from influenza virus hemagglutinin have potential as endosomal escape-inducing components in peptide-based drug delivery. Polarized light spectroscopy and tryptophan fluorescence were used to assess the conformation, orientation, effect on lipid order, and binding kinetics of wild-type peptide HA 1-23) and a glutamic acid-enriched analogue (INF7) in large unilamellar POPC or POPC/POPG (4:1) lipid vesicles (LUVs). pH-sensitive membrane leakage was established for INF7 but not HA2(1-23) using an entrapped-dye assay. A correlation is indicated between leakage and a low degree of lipid chain order (assessed by linear dichroism, LD, of the membrane orientation probe retinoic acid). Both peptides display poor alignment in zwitterionic POPC LUVs compared to POPC/POPG (4:1) LUVs, and it was found that peptide-lipid interactions display slow kinetics (hours), resulting in reduced lipid order and increased tryptophan shielding. At pH 7.4, INF7 displays tryptophan emission and LD features indicative of a surface-orientated peptide, suggesting that its N-terminal glutamic acid residues prevent deep penetration into the hydrocarbon core. At pH 5.0, INF7 displays weaker LD signals, indicating poor orientation, possibly due to aggregation. By contrast, the orientation of the HA2(1-23) peptide backbone supports previously reported oblique insertion (∼60-65° relative to the membrane normal), and aromatic side-chain orientations are consistent with an interfacial (pH-independent) location of the C-terminus. We propose that a conformational change upon reduction of pH is limited to minor rearrangements of the peptide "hinge region" around Trp14 and repositioning of this residue

  • 38. Gallego-Villarejo, Lucía
    et al.
    Wallin, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Król, Sylwia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Enrich-Bengoa, Jennifer
    Suades, Albert
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Universitat Autònoma de Barcelona, Spain.
    Aguilella-Arzo, Marcel
    Gomara, María José
    Haro, Isabel
    Wärmlander, Sebastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Muñoz, Francisco J.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Perálvarez-Marín, Alex
    Big dynorphin is a neuroprotector scaffold against amyloid β-peptide aggregation and cell toxicity2022Ingår i: Computational and Structural Biotechnology Journal, E-ISSN 2001-0370, Vol. 20, s. 5672-5679Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Amyloid β-peptide (Aβ) misfolding into β-sheet structures triggers neurotoxicity inducing Alzheimer’s disease (AD). Molecules able to reduce or to impair Aβ aggregation are highly relevant as possible AD treatments since they should protect against Aβ neurotoxicity. We have studied the effects of the interaction of dynorphins, a family of opioid neuropeptides, with Aβ40 the most abundant species of Aβ. Biophysical measurements indicate that Aβ40 interacts with Big Dynorphin (BigDyn), lowering the amount of hydrophobic aggregates, and slowing down the aggregation kinetics. As expected, we found that BigDyn protects against Aβ40 aggregates when studied in human neuroblastoma cells by cell survival assays. The cross-interaction between BigDyn and Aβ40 provides insight into the mechanism of amyloid pathophysiology and may open up new therapy possibilities.

  • 39.
    Georgieva, Elka R.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Narvaez, Ana Julia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Hedin, Niklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för fysikalisk kemi, oorganisk kemi och strukturkemi.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Secondary structure conversions of Mycobacterium tuberculosis ribonucleotide reductase protein R2 under varying pH and temperature conditions2008Ingår i: Biophysical Chemistry, Vol. 137, nr 43-48Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The structural properties of Mycobacterium tuberculosis (Mtb) ribonucleotide reductase R2 protein were studied under varying pH and temperature conditions by circular dichroism (CD) spectroscopy as well as dynamic light scattering (DLS). Under physiological conditions this protein has a high alpha-helical content, similar to the corresponding protein from other species, e.g. mouse. Decreasing the pH induced significant structure conversions. When pH was below 6.5 an aggregated structure was observed and reached a maximum at pH 4. The aggregated state of this protein was verified by DLS and was found to be rich in beta-structure. This amyloid-like structure transformed into a molten globule state with high temperature stability (between 25 and 80 degrees C) at pH below 3. The corresponding mouse protein R2 under similar conditions showed no evidence of an aggregated state around pH 4.

  • 40. Ghalebani, Leila
    et al.
    Wahlström, Anna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    pH dependence of the specific binding of Cu(II) and Zn(II) ions to the amyloid β peptideManuskript (preprint) (Övrigt vetenskapligt)
  • 41.
    Ghalebani, Leila
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wahlström, Anna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    pH-dependence of the specific binding of Cu(II) and Zn(II) ions to the amyloid-beta peptide2012Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 421, nr 3, s. 554-560Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Metal ions like Cu(II) and Zn(II) are accumulated in Alzheimer's disease amyloid plaques. The amyloid-beta (A beta) peptide involved in the disease interacts with these metal ions at neutral pH via ligands provided by the N-terminal histidines and the N-terminus. The present study uses high-resolution NMR spectroscopy to monitor the residue-specific interactions of Cu(II) and Zn(II) with N-15- and C-13,N-15-labeled A beta(1-40) peptides at varying pH levels. At pH 7.4 both ions bind to the specific ligands, competing with one another. At pH 5.5 Cu(II) retains its specific histidine ligands, while Zn(II) seems to lack residue-specific interactions. The low pH mimics acidosis which is linked to inflammatory processes in vivo. The results suggest that the cell toxic effects of redox active Cu(II) binding to AD may be reversed by the protective activity of non-redox active Zn(II) binding to the same major binding site under non-acidic conditions. Under acidic conditions, the protective effect of Zn(II) may be decreased or changed, since Zn(II) is less able to compete with Cu(II) for the specific binding site on the AD peptide under these conditions.

  • 42. Gielnik, Maciej
    et al.
    Szymańska, Aneta
    Dong, Xiaolin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. The National Institute of Chemical Physics and Biophysics, Estonia.
    Svedružić, Željko M.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kozak, Maciej
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Prion Protein Octarepeat Domain Forms Transient β-Sheet Structures upon Residue-Specific Binding to Cu(II) and Zn(II) Ions2023Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 62, nr 11, s. 1689-1705Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Misfolding of the cellular prion protein (PrPC) is associated with the development of fatal neurodegenerative diseases called transmissible spongiform encephalopathies (TSEs). Metal ions appear to play a crucial role in PrPC misfolding. PrPC is a combined Cu(II) and Zn(II) metal-binding protein, where the main metal-binding site is located in the octarepeat (OR) region. Thus, the biological function of PrPC may involve the transport of divalent metal ions across membranes or buffering concentrations of divalent metal ions in the synaptic cleft. Recent studies have shown that an excess of Cu(II) ions can result in PrPC instability, oligomerization, and/or neuroinflammation. Here, we have used biophysical methods to characterize Cu(II) and Zn(II) binding to the isolated OR region of PrPC. Circular dichroism (CD) spectroscopy data suggest that the OR domain binds up to four Cu(II) ions or two Zn(II) ions. Binding of the first metal ion results in a structural transition from the polyproline II helix to the β-turn structure, while the binding of additional metal ions induces the formation of β-sheet structures. Fluorescence spectroscopy data indicate that the OR region can bind both Cu(II) and Zn(II) ions at neutral pH, but under acidic conditions, it binds only Cu(II) ions. Molecular dynamics simulations suggest that binding of either metal ion to the OR region results in the formation of β-hairpin structures. As the formation of β-sheet structures can be a first step toward amyloid formation, we propose that high concentrations of either Cu(II) or Zn(II) ions may have a pro-amyloid effect in TSE diseases.

  • 43. Gielnik, Maciej
    et al.
    Taube, Michał
    Zhukova, Lilia
    Zhukov, Igor
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Svedružić, Željko
    Kwiatek, Wojciech M.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kozak, Maciej
    Zn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein2021Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 11, nr 1, artikel-id 21703Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The cellular prion protein (PrP(C)) is a mainly alpha-helical 208-residue protein located in the pre- and postsynaptic membranes. For unknown reasons, PrP(C) can undergo a structural transition into a toxic, beta-sheet rich scrapie isoform (PrPSc) that is responsible for transmissible spongiform encephalopathies (TSEs). Metal ions seem to play an important role in the structural conversion. PrP(C) binds Zn(II) ions and may be involved in metal ion transport and zinc homeostasis. Here, we use multiple biophysical techniques including optical and NMR spectroscopy, molecular dynamics simulations, and small angle X-ray scattering to characterize interactions between human PrP(C) and Zn(II) ions. Binding of a single Zn(II) ion to the PrP(C) N-terminal domain via four His residues from the octarepeat region induces a structural transition in the C-terminal alpha-helices 2 and 3, promotes interaction between the N-terminal and C-terminal domains, reduces the folded protein size, and modifies the internal structural dynamics. As our results suggest that PrP(C) can bind Zn(II) under physiological conditions, these effects could be important for the physiological function of PrP(C).

  • 44. Gielnik, Maciej
    et al.
    Zhukova, Lilia
    Zhukov, Igor
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kozak, Maciej
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The engineered peptide construct NCAM1-Aβ inhibits fibrillization of the human prion protein (PrP)2022Ingår i: Acta Biochimica Polonica, ISSN 0001-527X, E-ISSN 1734-154X, Vol. 69, nr 1, s. 257-261Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In prion diseases, the prion protein (PrP) becomes misfolded and forms fibrillar aggregates that are responsible for prion infectivity and pathology. So far, no drug or treatment procedures have been approved for prion disease treatment. We have previously shown that engineered cell-penetrating peptide constructs can reduce the amount of prion aggregates in infected cells. However, the molecular mechanism underlying this effect is unknown. Here, we use atomic force microscopy (AFM) imaging to show that the amyloid aggregation and fibrillization of the human PrP protein can be inhibited by equimolar amounts of the 25 residues long engineered peptide construct NCAM1-Aβ. 

  • 45.
    Griese, Julia J.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Roos, Katarina
    Stockholms universitet, Naturvetenskapliga fakulteten, Fysikum.
    Cox, Nicholas
    Shafaat, Hannah S.
    Branca, Rui M. M.
    Lehtio, Janne
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Lubitz, Wolfgang
    Siegbahn, Per E. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Fysikum.
    Högbom, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Direct observation of structurally encoded metal discrimination and ether bond formation in a heterodinuclear metalloprotein2013Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, nr 43, s. 17189-17194Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although metallocofactors are ubiquitous in enzyme catalysis, how metal binding specificity arises remains poorly understood, especially in the case of metals with similar primary ligand preferences such as manganese and iron. The biochemical selection of manganese over iron presents a particularly intricate problem because manganese is generally present in cells at a lower concentration than iron, while also having a lower predicted complex stability according to the Irving-Williams series (Mn-II < Fe-II < Ni-II < Co-II < Cu-II > Zn-II). Here we show that a heterodinuclear Mn/Fe cofactor with the same primary protein ligands in both metal sites self-assembles from MnII and FeII in vitro, thus diverging from the Irving-Williams series without requiring auxiliary factors such as metallochaperones. Crystallographic, spectroscopic, and computational data demonstrate that one of the two metal sites preferentially binds FeII over MnII as expected, whereas the other site is nonspecific, binding equal amounts of both metals in the absence of oxygen. Oxygen exposure results in further accumulation of the Mn/Fe cofactor, indicating that cofactor assembly is at least a two-step process governed by both the intrinsic metal specificity of the protein scaffold and additional effects exerted during oxygen binding or activation. We further show that the mixed-metal cofactor catalyzes a two-electron oxidation of the protein scaffold, yielding a tyrosine-valine ether cross-link. Theoretical modeling of the reaction by density functional theory suggests a multistep mechanism including a valyl radical intermediate.

  • 46.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Biophysical studies of model membrane interactions of cell penetrating peptides2007Konferensbidrag (Övrig (populärvetenskap, debatt, mm))
  • 47.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ribonucleotide reductase - a free radical enzyme2007Konferensbidrag (Övrig (populärvetenskap, debatt, mm))
  • 48.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ribonucleotide reductase - EPR studies of free radicals and redox-active metal sites2007Konferensbidrag (Övrig (populärvetenskap, debatt, mm))
  • 49.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ribonucleotide reductase - interplay between redox-active metals and free radicals2007Konferensbidrag (Övrig (populärvetenskap, debatt, mm))
  • 50.
    Gräslund, Astrid
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Danielsson, Jens
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    Pierattelli, R.
    Banci, L.
    Metal ion interaction with the Alzheimer A-beta peptide2007Konferensbidrag (Övrig (populärvetenskap, debatt, mm))
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