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  • 1. Abramsson, Mia L.
    et al.
    Sahin, Cagla
    Hopper, Jonathan T. S.
    Branca, Rui M. M.
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Xu, Mingming
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Chandler, Shane A.
    Österlund, Nicklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ilag, Leopold L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Leppert, Axel
    Costeira-Paulo, Joana
    Lang, Lisa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Teilum, Kaare
    Laganowsky, Arthur
    Benesch, Justin L. P.
    Oliveberg, Mikael
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Robinson, Carol V.
    Marklund, Erik G.
    Allison, Timothy M.
    Winther, Jakob R.
    Landreh, Michael
    Charge Engineering Reveals the Roles of Ionizable Side Chains in Electrospray Ionization Mass Spectrometry2021Inngår i: JACS Au, E-ISSN 2691-3704, Vol. 1, nr 12, s. 2385-2393Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In solution, the charge of a protein is intricately linked to its stability, but electrospray ionization distorts this connection, potentially limiting the ability of native mass spectrometry to inform about protein structure and dynamics. How the behavior of intact proteins in the gas phase depends on the presence and distribution of ionizable surface residues has been difficult to answer because multiple chargeable sites are present in virtually all proteins. Turning to protein engineering, we show that ionizable side chains are completely dispensable for charging under native conditions, but if present, they are preferential protonation sites. The absence of ionizable side chains results in identical charge state distributions under native-like and denaturing conditions, while coexisting conformers can be distinguished using ion mobility separation. An excess of ionizable side chains, on the other hand, effectively modulates protein ion stability. In fact, moving a single ionizable group can dramatically alter the gas-phase conformation of a protein ion. We conclude that although the sum of the charges is governed solely by Coulombic terms, their locations affect the stability of the protein in the gas phase.

  • 2. Kaldmae, Margit
    et al.
    Österlund, Nicklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Lianoudaki, Danai
    Sahin, Cagla
    Bergman, Peter
    Nyman, Tomas
    Kronqvist, Nina
    Ilag, Leopold L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Allison, Timothy M.
    Marklund, Erik G.
    Landreh, Michael
    Gas-Phase Collisions with Trimethylamine-N-Oxide Enable Activation-Controlled Protein Ion Charge Reduction2019Inngår i: Journal of the American Society for Mass Spectrometry, ISSN 1044-0305, E-ISSN 1879-1123, Vol. 30, nr 8, s. 1385-1388Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Modulating protein ion charge is a useful tool for the study of protein folding and interactions by electrospray ionization mass spectrometry. Here, we investigate activation-dependent charge reduction of protein ions with the chemical chaperone trimethylamine-N-oxide (TMAO). Based on experiments carried out on proteins ranging from 4.5 to 35kDa, we find that when combined with collisional activation, TMAO removes approximately 60% of the charges acquired under native conditions. Ion mobility measurements furthermore show that TMAO-mediated charge reduction produces the same end charge state and arrival time distributions for native-like and denatured protein ions. Our results suggest that gas-phase collisions between the protein ions and TMAO result in proton transfer, in line with previous findings for dimethyl- and trimethylamine. By adjusting the energy of the collisions experienced by the ions, it is possible to control the degree of charge reduction, making TMAO a highly dynamic charge reducer that opens new avenues for manipulating protein charge states in ESI-MS and for investigating the relationship between protein charge and conformation.

  • 3. Kaldmäe, Margit
    et al.
    Vosselman, Thibault
    Zhong, Xueying
    Lama, Dilraj
    Chen, Gefei
    Saluri, Mihkel
    Kronqvist, Nina
    Siau, Jia Wei
    Ng, Aik Seng
    Ghadessy, Farid J.
    Sabatier, Pierre
    Vojtesek, Borivoj
    Sarr, Médoune
    Sahin, Cagla
    Österlund, Nicklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ilag, Leopold L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Väänänen, Venla A.
    Sedimbi, Saikiran
    Arsenian-Henriksson, Marie
    Zubarev, Roman A.
    Nilsson, Lennart
    Koeck, Philip J. B.
    Rising, Anna
    Abelein, Axel
    Fritz, Nicolas
    Johansson, Jan
    Lane, David P.
    Landreh, Michael
    A “spindle and thread” mechanism unblocks p53 translation by modulating N-terminal disorder2022Inngår i: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 30, nr 5, s. 733-742, e1-e7Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Disordered proteins pose a major challenge to structural biology. A prominent example is the tumor suppressor p53, whose low expression levels and poor conformational stability hamper the development of cancer therapeutics. All these characteristics make it a prime example of “life on the edge of solubility.” Here, we investigate whether these features can be modulated by fusing the protein to a highly soluble spider silk domain (NT). The chimeric protein displays highly efficient translation and is fully active in human cancer cells. Biophysical characterization reveals a compact conformation, with the disordered transactivation domain of p53 wrapped around the NT domain. We conclude that interactions with NT help to unblock translation of the proline-rich disordered region of p53. Expression of partially disordered cancer targets is similarly enhanced by NT. In summary, we demonstrate that inducing co-translational folding via a molecular “spindle and thread” mechanism unblocks protein translation in vitro.

  • 4. Khaled, Mohammed
    et al.
    Rönnbäck, Isabel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ilag, Leopold L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Strodel, Birgit
    Österlund, Nicklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK). Karolinska Institutet, Sweden.
    A Hairpin Motif in the Amyloid-& beta Peptide Is Important for Formation of Disease-Related Oligomers2023Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 145, nr 33, s. 18340-18354Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The amyloid-& beta;(A & beta;) peptide is associated with the developmentof Alzheimer's disease and is known to form highly neurotoxicprefibrillar oligomeric aggregates, which are difficult to study dueto their transient, low-abundance, and heterogeneous nature. To obtainhigh-resolution information about oligomer structure and dynamicsas well as relative populations of assembly states, we here employa combination of native ion mobility mass spectrometry and moleculardynamics simulations. We find that the formation of A & beta; oligomersis dependent on the presence of a specific & beta;-hairpin motif inthe peptide sequence. Oligomers initially grow spherically but startto form extended linear aggregates at oligomeric states larger thanthose of the tetramer. The population of the extended oligomers couldbe notably increased by introducing an intramolecular disulfide bond,which prearranges the peptide in the hairpin conformation, therebypromoting oligomeric structures but preventing conversion into maturefibrils. Conversely, truncating one of the & beta;-strand-formingsegments of A & beta; decreased the hairpin propensity of the peptideand thus decreased the oligomer population, removed the formationof extended oligomers entirely, and decreased the aggregation propensityof the peptide. We thus propose that the observed extended oligomerstate is related to the formation of an antiparallel sheet state,which then nucleates into the amyloid state. These studies provideincreased mechanistic understanding of the earliest steps in A & beta;aggregation and suggest that inhibition of A & beta; folding into thehairpin conformation could be a viable strategy for reducing the amountof toxic oligomers.

  • 5.
    Król, Sylwia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Österlund, Nicklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Vosough, Faraz
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Barth, Andreas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ilag, Leopold Luna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Magzoub, Mazin
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mörman, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The amyloid-inhibiting NCAM-PrP peptide targets Aβ peptide aggregation in membrane-mimetic environments2021Inngår i: iScience, E-ISSN 2589-0042 , Vol. 24, nr 8, artikkel-id 102852Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Substantial research efforts have gone into elucidating the role of protein misfolding and self-assembly in the onset and progression of Alzheimer’s disease (AD). Aggregation of the Amyloid-β (Aβ) peptide into insoluble fibrils is closely associated with AD. Here, we use biophysical techniques to study a peptide-based approach to target Aβ amyloid aggregation. A peptide construct, NCAM-PrP, consists of a largely hydrophobic signal sequence linked to a positively charged hexapeptide. The NCAM-PrP peptide inhibits Aβ amyloid formation by forming aggregates which are unavailable for further amyloid aggregation. In a membrane-mimetic environment, Aβ and NCAM-PrP form specific heterooligomeric complexes, which are of lower aggregation states compared to Aβ homooligomers. The Aβ:NCAM-PrP interaction appears to take place on different aggregation states depending on the absence or presence of a membrane-mimicking environment. These insights can be useful for the development of potential future therapeutic strategies targeting Aβ at several aggregation states.

  • 6. Liu, Chang
    et al.
    Henning-Knechtel, Anja
    Österlund, Nicklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wu, Jinming
    Wang, Guangshun
    Gräslund, Rut Astrid Olivia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kirmizialtin, Serdal
    Luo, Jinghui
    Oligomer Dynamics of LL-37 Truncated Fragments Probed by α-Hemolysin Pore and Molecular Simulations2023Inngår i: Small, ISSN 1613-6810, E-ISSN 1613-6829, Vol. 19, nr 37, artikkel-id 2206232Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oligomerization of antimicrobial peptides (AMPs) is critical in their effects on pathogens. LL-37 and its truncated fragments are widely investigated regarding their structures, antimicrobial activities, and application, such as developing new antibiotics. Due to the small size and weak intermolecular interactions of LL-37 fragments, it is still elusive to establish the relationship between oligomeric states and antimicrobial activities. Here, an α-hemolysin nanopore, mass spectrometry (MS), and molecular dynamic (MD) simulations are used to characterize the oligomeric states of two LL-37 fragments. Nanopore studies provide evidence of trapping events related to the oligomer formation and provide further details on their stabilities, which are confirmed by MS and MD simulations. Furthermore, simulation results reveal the molecular basis of oligomer dynamics and states of LL-37 fragments. This work provides unique insights into the relationship between the oligomer dynamics of AMPs and their antimicrobial activities at the single-molecule level. The study demonstrates how integrating methods allows deciphering single molecule level understanding from nanopore sensing approaches. 

  • 7. Liu, Lin
    et al.
    Dong, Xin
    Liu, Yichang
    Österlund, Nicklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Carloni, Paolo
    Li, Jinyu
    Role of hydrophobic residues for the gaseous formation of helical motifs2019Inngår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 55, nr 35, s. 5147-5150Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The secondary structure content of proteins and their complexes may change significantly on passing from aqueous solution to the gas phase (as in mass spectrometry experiments). In this work, we investigate the impact of hydrophobic residues on the formation of the secondary structure of a real protein complex in the gas phase. We focus on a well-studied protein complex, the amyloid- (1-40) dimer (2A). Molecular dynamics simulations reproduce the results of ion mobility-mass spectrometry experiments. In addition, a helix (not present in the solution) is identified involving (19)FFAED(23), consistent with infrared spectroscopy data on an A segment. Our simulations further point to the role of hydrophobic residues in the formation of helical motifs - hydrophobic sidechains shield helices from being approached by residues that carry hydrogen bond sites. In particular, two hydrophobic phenylalanine residues, F19 and F20, play an important role for the helix, which is induced in the gas phase in spite of the presence of two carboxyl-containing residues.

  • 8.
    Riboni, Nicolò
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi. University of Parma, Italy.
    Quaranta, Alessandro
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Motwani, Hitesh
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Österlund, Nicklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Bianchi, Federica
    Ilag, Leopold
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Solvent-Assisted Paper Spray Ionization (SAPSI) for the Analysis of Biomolecules and BiofluidsManuskript (preprint) (Annet vitenskapelig)
  • 9.
    Riboni, Nicoló
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi. University of Parma, Italy.
    Quaranta, Alessandro
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Motwani, Hitesh
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Österlund, Nickles
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Bianchi, Federica
    Ilag, Leopold L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Solvent-Assisted Paper Spray Ionization Mass Spectrometry (SAPSI-MS) for the Analysis of Biomolecules and Biofluids2019Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 9, artikkel-id 10296Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Paper Spray Ionization (PSI) is commonly applied for the analysis of small molecules, including drugs, metabolites, and pesticides in biological fluids, due to its high versatility, simplicity, and low costs. In this study, a new setup called Solvent Assisted Paper Spray Ionization (SAPSI), able to increase data acquisition time, signal stability, and repeatability, is proposed to overcome common PSI drawbacks. The setup relies on an integrated solution to provide ionization potential and constant solvent flow to the paper tip. Specifically, the ion source was connected to the instrument fluidics along with the voltage supply systems, ensuring a close control over the ionization conditions. SAPSI was successfully applied for the analysis of different classes of biomolecules: amyloidogenic peptides, proteins, and N-glycans. The prolonged analysis time allowed real-time monitoring of processes taking places on the paper tip, such as amyloid peptides aggregation and disaggregation phenomena. The enhanced signal stability allowed to discriminate protein species characterized by different post translational modifications and adducts with electrophilic compounds, both in aqueous solutions and in biofluids, such as serum and cerebrospinal fluid, without any sample pretreatment. In the next future, application to clinical relevant modifications, could lead to the development of quick and cost-effective diagnostic tools.

  • 10. Sahin, Cagla
    et al.
    Österlund, Nicklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Leppert, Axel
    Johansson, Jan
    Marklund, Erik G.
    Benesch, Justin L. P.
    Ilag, Leopold L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Allison, Timothy M.
    Landreh, Michael
    Ion mobility-mass spectrometry shows stepwise protein unfolding under alkaline conditions2021Inngår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 57, nr 12, s. 1450-1453Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Although native mass spectrometry is widely applied to monitor chemical or thermal protein denaturation, it is not clear to what extent it can inform about alkali-induced unfolding. Here, we probe the relationship between solution- and gas-phase structures of proteins under alkaline conditions. Native ion mobility-mass spectrometry reveals that globular proteins are destabilized rather than globally unfolded, which is supported by solution studies, providing detailed insights into alkali-induced unfolding events. Our results pave the way for new applications of MS to monitor structures and interactions of proteins at high pH.

  • 11. Sahin, Cagla
    et al.
    Østerlund, Eva Christina
    Österlund, Nicklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Costeira-Paulo, Joana
    Nedergaard Pedersen, Jannik
    Christiansen, Gunna
    Nielsen, Janni
    Grønnemose, Anne Louise
    Kirk Amstrup, Søren
    Tiwari, Manish K.
    Rao, R. Shyama Prasad
    Bjerrum, Morten Jannik
    Ilag, Leopold L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Davies, Michael J.
    Marklund, Erik G.
    Pedersen, Jan Skov
    Landreh, Michael
    Møller, Ian Max
    Jørgensen, Thomas J. D.
    Otzen, Daniel Erik
    Structural Basis for Dityrosine-Mediated Inhibition of α-Synuclein Fibrillization2022Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 144, nr 27, s. 11949-11954Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    α-Synuclein (α-Syn) is an intrinsically disordered protein which self-assembles into highly organized β-sheet structures that accumulate in plaques in brains of Parkinson’s disease patients. Oxidative stress influences α-Syn structure and self-assembly; however, the basis for this remains unclear. Here we characterize the chemical and physical effects of mild oxidation on monomeric α-Syn and its aggregation. Using a combination of biophysical methods, small-angle X-ray scattering, and native ion mobility mass spectrometry, we find that oxidation leads to formation of intramolecular dityrosine cross-linkages and a compaction of the α-Syn monomer by a factor of √2. Oxidation-induced compaction is shown to inhibit ordered self-assembly and amyloid formation by steric hindrance, suggesting an important role of mild oxidation in preventing amyloid formation. 

  • 12.
    Wallin, Cecilia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Sholts, Sabrina B.
    Österlund, Nicklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Luo, Jinghui
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. The National Institute of Chemical Physics and Biophysics, Estonia.
    Roos, Per M.
    Ilag, Leopold
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    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.
    Alzheimer's disease and cigarette smoke components: effects of nicotine, PAHs, and Cd(II), Cr(III), Pb(II), Pb(IV) ions on amyloid-beta peptide aggregation2017Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 7, artikkel-id 14423Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cigarette smoking is a significant risk factor for Alzheimer’s disease (AD), which is associated with extracellular brain deposits of amyloid plaques containing aggregated amyloid-β (Aβ) peptides. Aβ aggregation occurs via multiple pathways that can be influenced by various compounds. Here, we used AFM imaging and NMR, fluorescence, and mass spectrometry to monitor in vitro how Aβ aggregation is affected by the cigarette-related compounds nicotine, polycyclic aromatic hydrocarbons (PAHs) with one to five aromatic rings, and the metal ions Cd(II), Cr(III), Pb(II), and Pb(IV). All PAHs and metal ions modulated the Aβ aggregation process. Cd(II), Cr(III), and Pb(II) ions displayed general electrostatic interactions with Aβ, whereas Pb(IV) ions showed specific transient binding coordination to the N-terminal Aβ segment. Thus, Pb(IV) ions are especially prone to interact with Aβ and affect its aggregation. While Pb(IV) ions affected mainly Aβ dimer and trimer formation, hydrophobic toluene mainly affected formation of larger aggregates such as tetramers. The uncharged and hydrophilic nicotine molecule showed no direct interactions with Aβ, nor did it affect Aβ aggregation. Our Aβ interaction results suggest a molecular rationale for the higher AD prevalence among smokers, and indicate that certain forms of lead in particular may constitute an environmental risk factor for AD.

  • 13. Wu, Jinming
    et al.
    Österlund, Nicklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Wang, Hongzhi
    Sternke-Hoffmann, Rebecca
    Pupart, Hegne
    Ilag, Leopold L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Luo, Jinghui
    Identifying the role of co-aggregation of Alzheimer's amyloid-beta with amorphous protein aggregates of non-amyloid proteins2022Inngår i: Cell Reports Physical Science, E-ISSN 2666-3864, Vol. 3, nr 9, artikkel-id 101028Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Protein homeostasis collapse typically leads to protein aggregation into amyloid fibrils and diffuse amorphous aggregates, which both occur in Alzheimer’s and other neurodegenerative diseases, but their relationship remains to be clarified. Here we examine the interactions between the amorphously aggregated non-chaperone proteins (albumin, β-lactoglobulin, and superoxide dismutase 1) and Alzheimer’s amyloid-β (Aβ) peptides. Amorphous aggregates suppress the primary nucleation and elongation of Aβ fibrillation and modulate Aβ toxicity. The higher inhibitory efficiency of intermediately sized molten globular aggregates (20–300 nm) on Aβ fibrillation is hypothesized to be due to the higher amount of exposed hydrophobic residues and higher free energy. The formed co-aggregates are off-pathway species that favor formation of the amorphous end state instead of fibrillar amyloid structures normally formed by Aβ. Our findings expand our knowledge of how the native and aggregated cellular proteins modulate Aβ aggregation at the molecular and mesoscopic level and point out the major conclusions.

  • 14.
    Wärmländer, Sebastian K. T. S.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Österlund, Nicklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wallin, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wu, Jinming
    Luo, Jinghui
    Tiiman, Ann
    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.
    Metal binding to the amyloid-beta peptides in the presence of biomembranes: potential mechanisms of cell toxicity2019Inngår i: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 24, nr 8, s. 1189-1196Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The amyloid-beta (A beta) peptides are key molecules in Alzheimer's disease (AD) pathology. They interact with cellular membranes, and can bind metal ions outside the membrane. Certain oligomeric A beta aggregates are known to induce membrane perturbations and the structure of these oligomers-and their membrane-perturbing effects-can be modulated by metal ion binding. If the bound metal ions are redox active, as e.g., Cu and Fe ions are, they will generate harmful reactive oxygen species (ROS) just outside the membrane surface. Thus, the membrane damage incurred by toxic A beta oligomers is likely aggravated when redox-active metal ions are present. The combined interactions between A beta oligomers, metal ions, and biomembranes may be responsible for at least some of the neuronal death in AD patients.

  • 15.
    Österlund, Nicklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Capturing transient peptide assemblies associated with Alzheimer's disease: Native mass spectrometry studies of amyloid-β oligomerization2023Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Correct folding of proteins is essential for maintaining a functional living cell. Misfolding and aggregation of proteins, where non-native intermolecular interactions form large and highly ordered amyloid aggregates with low free energy, is hence associated with multiple diseases. One example is Alzheimer’s disease (AD) where the Amyloid-β (Aβ) peptide aggregates into amyloid fibrils, which deposit as neuritic plaques in the brains of AD patients. Nucleation of amyloid fibrils takes place via formation of smaller pre-nucleation clusters, so-called oligomers, which are considered to be especially toxic and are therefore potentially important in AD pathology. Detailed mechanistic molecular knowledge of Aβ aggregation is important for design of AD treatments that target these processes. The oligomeric species are however challenging to study experimentally due to their low abundance and high polydispersity.  

    Aβ oligomers are in this thesis studied under controlled in vitro conditions using bottom-up biophysics. Highly pure recombinant Aβ peptides are studied, primarily using native ion-mobility mass spectrometry, to monitor the spontaneous formation of oligomers in aqueous solution. Mass spectrometry is capable of resolving individual oligomeric states, while ion mobility provides low-resolution structure information. This is complemented with other biophysical techniques, as well as theoretical modeling. The oligomers are also studied upon modulating intrinsic factors, such as peptide length and sequence, or extrinsic factors, such as the chemical environment. Interactions with two important biological interaction partners are studied: chaperone proteins and cell membranes.  

    We show how Aβ oligomers assemble, and form extended structures which may be linked to continued growth into amyloid fibrils. We also show how different amyloid chaperone proteins interact with growing aggregates, which modifies and delays the aggregation process. These interactions are shown to depend on specific sequence-motifs in the chaperones and client peptides. Membrane-mimicking micelles are on the other hand able to stabilize globular compact forms of the Aβ oligomers and to inhibit the formation of extended structures which nucleate into amyloid fibrils. This may contribute to enrichment of toxic species in vivo. Interactions with membrane-mimicking systems are shown to be highly dependent on both the Aβ peptide isoform and the properties of the membrane environment, such as headgroup charges. It is also demonstrated how addition of a designed small peptide construct can inhibit formation of Aβ oligomers in the membrane environment. 

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  • 16.
    Österlund, Nicklas
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Frankel, Rebecca
    Lund University, Department of Chemistry, Division of Biochemistry and Structural Biology .
    Carlsson, Andreas
    Lund University, Department of Chemistry, Division of Biochemistry and Structural Biology .
    Thacker, Dev
    Lund University, Department of Chemistry, Division of Biochemistry and Structural Biology .
    Karlsson, Maja
    Lund University, Department of Chemistry, Division of Biochemistry and Structural Biology .
    Matus, Vanessa
    Lund University, Department of Chemistry, Division of Biochemistry and Structural Biology .
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Emanuelsson, Cecilia
    Lund University, Department of Chemistry, Division of Biochemistry and Structural Biology .
    Linse, Sara
    Lund University, Department of Chemistry, Division of Biochemistry and Structural Biology .
    The C-terminal domain of the anti-amyloid chaperone DNAJB6 binds to Amyloid-β peptide fibrils and inhibits secondary nucleationManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The DNAJB6 chaperone inhibits fibril formation of aggregation-prone client peptides through interaction with aggregated and oligomeric forms of the amyloid peptides. Its C-terminal domain (CTD) is believed to be functionally important, which is here studied using a set of constructs, either comprising the entire CTD or the first two or all four of the β-strands in the CTD grafted onto a scaffold protein. Each construct was expressed as wild-type and as a mutant variant with alanines replacing five highly conserved and functionally important serine and threonine residues in the first β-strand. The stability, oligomerization, anti-amyloid activity, and affinity for Amyloid-β (Aβ42) species was explored for the constructs using optical spectroscopy, native mass spectrometry, chemical crosslinking and surface plasmon resonance technology. While DNAJB6 forms large and polydisperse oligomers, CTD was found to form only monomers, dimers and tetramers. The dimerization and thermal stability of CTD are significantly reduced by the alanine substitutions. Kinetic analyses show a shift in inhibition mechanism. Full-length DNAJB6 efficiently inhibits primary and secondary nucleation, while all CTD constructs inhibited secondary nucleation but not primary nucleation. Moreover, the anti-amyloid activity of the CTD constructs was not dependent on the serine and threonine residues in the first β-strand. Our findings indicate that the inhibition of primary nucleation in full length DNAJB6 may be due to its high chemical potential and thus its propensity to form oligomers and co-oligomers with Aβ. The CTD constructs instead only bind to Aβ42 fibrils, which affects the nucleation events at the fibril surface.

  • 17.
    Österlund, Nicklas
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Frankel, Rebecca
    Carlsson, Andreas
    Thacker, Dev
    Karlsson, Maja
    Matus, Vanessa
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Emanuelsson, Cecilia
    Linse, Sara
    The C-terminal domain of the antiamyloid chaperone DNAJB6 binds to amyloid-β peptide fibrils and inhibits secondary nucleation2023Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 299, nr 11, artikkel-id 105317Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The DNAJB6 chaperone inhibits fibril formation of aggregation-prone client peptides through interaction with aggregated and oligomeric forms of the amyloid peptides. Here, we studied the role of its C-terminal domain (CTD) using constructs comprising either the entire CTD or the first two or all four of the CTD β-strands grafted onto a scaffold protein. Each construct was expressed as WT and as a variant with alanines replacing five highly conserved and functionally important serine and threonine residues in the first β-strand. We investigated the stability, oligomerization, antiamyloid activity, and affinity for amyloid-β (Aβ42) species using optical spectroscopy, native mass spectrometry, chemical crosslinking, and surface plasmon resonance technology. While DNAJB6 forms large and polydisperse oligomers, CTD was found to form only monomers, dimers, and tetramers of low affinity. Kinetic analyses showed a shift in inhibition mechanism. Whereas full-length DNAJB6 activity is dependent on the serine and threonine residues and efficiently inhibits primary and secondary nucleation, all CTD constructs inhibit secondary nucleation only, independently of the serine and threonine residues, although their dimerization and thermal stabilities are reduced by alanine substitution. While the full-length DNAJB6 inhibition of primary nucleation is related to its propensity to form coaggregates with Aβ, the CTD constructs instead bind to Aβ42 fibrils, which affects the nucleation events at the fibril surface. The retardation of secondary nucleation by DNAJB6 can thus be ascribed to the first two β-strands of its CTD, whereas the inhibition of primary nucleation is dependent on the entire protein or regions outside the CTD.

  • 18.
    Österlund, Nicklas
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Khaled, Mohammed
    Institute of Biological Information Processing: Structural Biochemistry (IBI-7), Forschungszentrum Jülich.
    Rönnbäck, Isabel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ilag, Leopold L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Strodel, Birgit
    Institute of Biological Information Processing: Structural Biochemistry (IBI-7), Forschungszentrum Jülich.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    A hairpin motif in the Amyloid-β peptide is important for formation of disease-related oligomersManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The Amyloid-β (Aβ) peptide is an aggregation-prone peptide linked to neurodegeneration in Alzheimer’s disease (AD). Aβ self-assembles spontaneously in aqueous solution to form aggregates of various sizes, with smaller pre-fibrillar oligomeric aggregates being especially neurotoxic. Such small oligomers are however difficult to study as they are transient, low abundant and heterogenous. We here use a combination of native ion mobility-mass spectrometry and molecular dynamics simulations to systematically study the structure and assembly mechanisms of Aβ oligomers in vitro. It is found that oligomers cannot be formed by a peptide variant that does not have propensity to fold into a β-hairpin motif present in the wild type Aβ peptide. This specific structure motif seems to be a more important determinant for aggregation than the overall hydrophobicity of the peptide. Introduction of an intramolecular disulfide bond in the Aβ peptide increases oligomerization, even though the monomeric peptide is not stabilized in the hairpin conformation. This is probably achieved by pre-arranging the peptide in a conformation which is compatible with oligomeric, but not fibrillar structures. As oligomerization is driven by formation of the hairpin motif it was furthermore possible to decrease the oligomer population by truncating one of the β-strands, and thus decreasing the hairpin propensity of the peptide. These studies provide increased understanding of the earliest steps in Aβ aggregation where species related to AD toxicity might be formed. Prevention of Aβ folding into the hairpin conformation, or specific binding to the hairpin motif could be strategies to design AD therapies. 

  • 19.
    Österlund, Nicklas
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Kulkarni, Yashraj S.
    Misiaszek, Agata D.
    Wallin, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Krüger, Dennis M.
    Liao, Qinghua
    Mashayekhy Rad, Farshid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Strodel, Birgit
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ilag, Leopold L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Kamerlin, Shina C. L.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Amyloid-beta Peptide Interactions with Amphiphilic Surfactants: Electrostatic and Hydrophobic Effects2018Inngår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 9, nr 7, s. 1680-1692Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The amphiphilic nature of the amyloid-beta (A beta) peptide associated with Alzheimer's disease facilitates various interactions with biomolecules such as lipids and proteins, with effects on both structure and toxicity of the peptide. Here, we investigate these peptide-amphiphile interactions by experimental and computational studies of A beta(1-40) in the presence of surfactants with varying physicochemical properties. Our findings indicate that electrostatic peptide-surfactant interactions are required for coclustering and structure induction in the peptide and that the strength of the interaction depends on the surfactant net charge. Both aggregation-prone peptide-rich coclusters and stable surfactant-rich coclusters can form. Only A beta(1-40) monomers, but not oligomers, are inserted into surfactant micelles in this surfactant-rich state. Surfactant headgroup charge is suggested to be important as electrostatic peptide-surfactant interactions on the micellar surface seems to be an initiating step toward insertion. Thus, no peptide insertion or change in peptide secondary structure is observed using a nonionic surfactant. The hydrophobic peptide-surfactant interactions instead stabilize the A beta monomer, possibly by preventing self-interaction between the peptide core and C terminus, thereby effectively inhibiting the peptide aggregation process. These findings give increased understanding regarding the molecular driving forces for A beta aggregation and the peptide interaction with amphiphilic biomolecules.

  • 20.
    Österlund, Nicklas
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Lundqvist, Martin
    Ilag, Leopold L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Emanuelsson, Cecilia
    Amyloid-β oligomers are captured by the DNAJB6 chaperone: Direct detection of interactions that can prevent primary nucleation2020Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 295, nr 24, s. 8135-8144Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A human molecular chaperone protein, DnaJ heat shock protein family (Hsp40) member B6 (DNAJB6), efficiently inhibits amyloid aggregation. This inhibition depends on a unique motif with conserved serine and threonine (S/T) residues that have a high capacity for hydrogen bonding. Global analysis of kinetics data has previously shown that DNAJB6 especially inhibits the primary nucleation pathways. These observations indicated that DNAJB6 achieves this remarkably effective and sub-stoichiometric inhibition by interacting not with the monomeric unfolded conformations of the amyloid-? symbol (A?) peptide but with aggregated species. However, these pre-nucleation oligomeric aggregates are transient and difficult to study experimentally. Here, we employed a native MS-based approach to directly detect oligomeric forms of A? formed in solution. We found that WT DNAJB6 considerably reduces the signals from the various forms of A? (1?40) oligomers, whereas a mutational DNAJB6 variant in which the S/T residues have been substituted with alanines does not. We also detected signals that appeared to represent DNAJB6 dimers and trimers to which varying amounts of A? are bound. These data provide direct experimental evidence that it is the oligomeric forms of A? that are captured by DNAJB6 in a manner which depends on the S/T residues. We conclude that, in agreement with the previously observed decrease in primary nucleation rate, strong binding of A? oligomers to DNAJB6 inhibits the formation of amyloid nuclei.

  • 21.
    Österlund, Nicklas
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Luo, Jinghui
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Membrane-mimetic systems for biophysical studies of the amyloid-beta peptide2019Inngår i: Biochimica et Biophysica Acta - Proteins and Proteomics, ISSN 1570-9639, E-ISSN 1878-1454, Vol. 1867, nr 5, s. 492-501Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The interplay between the amyloid-beta (A beta) peptide and cellular membranes have been proposed as an important mechanism for toxicity in Alzheimer's disease (AD). Membrane environments appear to influence A beta aggregation and may stabilize intermediate A beta oligomeric states that are considered to be neurotoxic. One important role for molecular biophysics within the field of A beta studies is to characterize the structure and dynamics of the A beta peptide in various states, as well as the kinetics of transfer between these states. Because biological cell membranes are very complex, simplified membrane models are needed to facilitate studies of A beta and other amyloid proteins in lipid environments. In this review, we examine different membrane-mimetic systems available for molecular studies of A beta. An introduction to each system is given, and examples of important findings are presented for each system. The benefits and drawbacks of each system are discussed from methodical and biological perspectives.

  • 22.
    Österlund, Nicklas
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Moons, Rani
    Ilag, Leopold L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Sobott, Frank
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Native Ion Mobility-Mass Spectrometry Reveals the Formation of beta-Barrel Shaped Amyloid-beta Hexamers in a Membrane-Mimicking Environment2019Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 141, nr 26, s. 10440-10450Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mechanisms behind the Amyloid-beta (A beta) peptide neurotoxicity in Alzheimer's disease are intensely studied and under debate. One suggested mechanism is that the peptides assemble in biological membranes to form beta-barrel shaped oligomeric pores that induce cell leakage. Direct detection of such putative assemblies and their exact oligomeric states is however complicated by a high level of heterogeneity. The theory consequently remains controversial, and the actual formation of pore structures is disputed. We herein overcome the heterogeneity problem by employing a native mass spectrometry approach and demonstrate that A beta(1-42) peptides form coclusters with membrane mimetic detergent micelles. The coclusters are gently ionized using nanoelectrospray and transferred into the mass spectrometer where the detergent molecules are stripped away using collisional activation. We show that A beta(1-42) indeed oligomerizes over time in the micellar environment, forming hexamers with collision cross sections in agreement with a general beta-barrel structure. We also show that such oligomers are maintained and even stabilized by addition of lipids. A beta(1-40) on the other hand form significantly lower amounts of oligomers, which are also of lower oligomeric state compared to A beta(1-42) oligomers. Our results thus support the oligomeric pore hypothesis as one important cell toxicity mechanism in Alzheimer's disease. The presented native mass spectrometry approach is a promising way to study such potentially very neurotoxic species and how they could be stabilized or destabilized by molecules of cellular or therapeutic relevance.

  • 23.
    Österlund, Nicklas
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Vosselman, Thibault
    Leppert, Axel
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jörnvall, Hans
    Ilag, Leopold L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Marklund, Erik G.
    Elofsson, Arne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Johansson, Jan
    Sahin, Cagla
    Landreh, Michael
    Mass Spectrometry and Machine Learning Reveal Determinants of Client Recognition by Antiamyloid Chaperones2022Inngår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 21, nr 10, artikkel-id 100413Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The assembly of proteins and peptides into amyloid fibrils is causally linked to serious disorders such as Alzheimer’s disease. Multiple proteins have been shown to prevent amyloid formation in vitro and in vivo, ranging from highly specific chaperone–client pairs to completely nonspecific binding of aggregation-prone peptides. The underlying interactions remain elusive. Here, we turn to the machine learning–based structure prediction algorithm AlphaFold2 to obtain models for the nonspecific interactions of β-lactoglobulin, transthyretin, or thioredoxin 80 with the model amyloid peptide amyloid β and the highly specific complex between the BRICHOS chaperone domain of C-terminal region of lung surfactant protein C and its polyvaline target. Using a combination of native mass spectrometry (MS) and ion mobility MS, we show that nonspecific chaperoning is driven predominantly by hydrophobic interactions of amyloid β with hydrophobic surfaces in β-lactoglobulin, transthyretin, and thioredoxin 80, and in part regulated by oligomer stability. For C-terminal region of lung surfactant protein C, native MS and hydrogen–deuterium exchange MS reveal that a disordered region recognizes the polyvaline target by forming a complementary β-strand. Hence, we show that AlphaFold2 and MS can yield atomistic models of hard-to-capture protein interactions that reveal different chaperoning mechanisms based on separate ligand properties and may provide possible clues for specific therapeutic intervention.

  • 24.
    Österlund, Nicklas
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Humanistiska fakulteten, Institutionen för arkeologi och antikens kultur. CellPept Sweden AB, Sweden.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. CellPept Sweden AB, Sweden.
    Cell-Penetrating Peptides with Unexpected Anti-Amyloid Properties2022Inngår i: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 14, nr 4, artikkel-id 823Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Cell-penetrating peptides (CPPs) with sequences derived originally from a prion protein (PrP) have been shown to exhibit both anti-prion and anti-amyloid properties particularly against prion proteins and the amyloid-β (Aβ) peptide active in Alzheimer’s disease. These disease-modifying properties are so far observed in cell cultures and in vitro. The CPP sequences are composed of a hydrophobic signal sequence followed by a highly positively charged hexapeptide segment. The original signal sequence of the prion protein can be changed to the signal sequence of the NCAM1 protein without losing the anti-prion activity. Although the detailed molecular mechanisms of these CPP peptides are not fully understood, they do form amyloid aggregates by themselves, and molecular interactions between the CPPs and PrP/Aβ can be observed in vitro using various spectroscopic techniques. These initial intermolecular interactions appear to re-direct the aggregation pathways for prion/amyloid formation to less cell-toxic molecular structures (i.e., co-aggregates), which likely is why the disease-inducing PrP/Aβ aggregation is counteracted in vivo.

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