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  • 1.
    Unnerståle, Sofia E.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Membrane Induced Structure in Transmembrane Signaling Proteins and Peptides: Peptide–Lipid Interactions Studied by Spectroscopic Methods2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Biological membranes, defining the boundary of cells and eukaryotic organelles, are mainly composed of lipids and membrane proteins. Interactions between these lipids and proteins are needed to preserve the tight seal of the membrane, but also to induce structure for proper function in many membrane proteins. In this thesis, interactions between three different kinds of peptides, i.e. small proteins, and model membranes are studied by spectroscopic methods.

    First, the membrane interaction of two paddle domains, KvAPp, from the voltage-gated potassium channel KvAP from Aeropyrum pernix, and HsapBKp, from the human, large conductance, calcium-activated potassium channel HsapBK, was studied (paper I and II). In paper I, a high-resolution solution NMR structure of HsapBKp in detergent micelles is presented revealing a helix-turn-helix motif. Small structural differences between HsapBKp and KvAPp, positioning the arginines differently, are presented. These structural differences may explain why BK channels are weakly voltage-gated. In paper II, it is shown that HsapBKp perturbs the membrane more than KvAPp and that the membrane perturbation is related to β-structure and to dynamics in the turn in the helix-turn-helix motif.

    Second, the membrane interaction of HAMP domains modulating transmission in prokaryotic transmembrane signaling was studied (paper III). Based on the membrane interaction of the AS1 segments of the HAMP domains, two groups were identified: one strongly membrane interacting and one weakly membrane interacting. The two groups are suggested to use different signaling mechanisms.

    Third, nonspecific binding of proinsulin C-peptide, the linker peptide connecting chain A and B in insulin, to model membranes was studied (paper IV). The study revealed that C-peptide binds to a model membrane at low pH, but the membrane induces no large structural rearrangements of the peptide. 

  • 2.
    Unnerståle, Sofia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lind, Jesper
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Papadopoulos, Evangelos
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mäler, Lena
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Solution structure of the HsapBK K+ channel voltage-sensor paddle sequence2009In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 48, no 25, p. 5813-5821Article in journal (Refereed)
    Abstract [en]

    Voltage-gated potassium channels open and close in response to changes in the membrane potential. In this study, we have determined the NMR solution structure of the putative S3b-S4 voltage-sensor paddle fragment, the part that moves to mediate voltage gating, of the HsapBK potassium channel in dodecylphosphocholine (DPC) micelles. This paper presents the first structure of the S3b-S4 fragment from a BK channel. Diffusion coefficients as determined from PFG NMR experiments showed that a well-defined complex between the peptide and DPC molecules was formed. The structure reveals a helix-turn-helix motif, which is in agreement with crystal structures of other voltage-gated potassium channels, thus indicating that it is feasible to study the isolated fragment. The paddle motifs generally contain several basic residues, implicated in the gating. The critical Arg residues in this structure all reside on the surface, which is in agreement with crystal structures of K(v) channels. Similarities in the structure of the S3b-S4 fragment in BK and K(v) channels as well as important differences are seen, which may be important for explaining the details in paddle movement within a bilayer.

  • 3.
    Unnerståle, Sofia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Madani, Fatemeh
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mäler, Lena
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Membrane-perturbing properties of two Arg-rich paddle domains from voltage-gated sensors in the KvAP and HsapBK K+ channels2012In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 51, no 19, p. 3982-3992Article in journal (Refereed)
    Abstract [en]

    Voltage-gated K+ channels are gated by displacement of basic residues located in the S4 helix that together with a part of the S3 helix, S3b, forms a “paddle” domain, whose position is altered by changes in the membrane potential modulating the open probability of the channel. Here, interactions between two paddle domains, KvAPp from the Kv channel from Aeropyrum pernix and HsapBKp from the BK channel from Homo sapiens, and membrane models have been studied by spectroscopy. We show that both paddle domains induce calcein leakage in large unilamellar vesicles, and we suggest that this leakage represents a general thinning of the bilayer, making movement of the whole paddle domain plausible. The fact that HsapBKp induces more leakage than KvAPp may be explained by the presence of a Trp residue in HsapBKp. Trp residues generally promote localization to the hydrophilic–hydrophobic interface and disturb tight packing. In magnetically aligned bicelles, KvAPp increases the level of order along the whole acyl chain, while HsapBKp affects the morphology, also indicating that KvAPp adapts more to the lipid environment. Nuclear magnetic resonance (NMR) relaxation measurements for HsapBKp show that overall the sequence has anisotropic motions. The S4 helix is well-structured with restricted local motion, while the turn between S4 and S3b is more flexible and undergoes slow local motion. Our results indicate that the calcein leakage is related to the flexibility in this turn region. A possibility by which HsapBKp can undergo structural transitions is also shown by relaxation NMR, which may be important for the gating mechanism.

  • 4.
    Unnerståle, Sofia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mäler, Lena
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    pH-Dependent Interaction between C-Peptide and Phospholipid Bicelles2012In: Journal of Biophysics, ISSN 1687-8019, p. 185907-Article in journal (Refereed)
    Abstract [en]

    C-peptide is the connecting peptide between the A and B chains of insulin in proinsulin. In this paper, we investigate the interaction between C-peptide and phospholipid bicelles, by circular dichroism and nuclear magnetic resonance spectroscopy, and in particular the pH dependence of this interaction. The results demonstrate that C-peptide is largely unstructured independent of pH, but that a weak structural induction towards a short stretch of β-sheet is induced at low pH, corresponding to the isoelectric point of the peptide. Furthermore, it is demonstrated that C-peptide associates with neutral phospholipid bicelles as well as acidic phospholipid bicelles at this low pH. C-peptide does not undergo a large structural rearrangement as a consequence of lipid interaction, which indicates that the folding and binding are uncoupled. In vivo, local variations in environment, including pH, may cause C-peptide to associate with lipids, which may affect the aggregation state of the peptide.

  • 5.
    Unnerståle, Sofia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mäler, Lena
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Draheim, Roger R.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Structural characterization of AS1-membrane interactions from a subset of HAMP domains2011In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1808, no 10, p. 2403-2412Article in journal (Refereed)
    Abstract [en]

    HAMP domains convert an extracellular sensory input into an intracellular signaling response in a wide variety of membrane-embedded bacterial proteins. These domains are almost invariably found adjacent to the inner leaflet of the cell membrane. We therefore examined the interaction of peptides corresponding to either AS1 or AS2 of four different, well-characterized HAMP domains with several membrane model systems. The proteins included an Archaeoglobus fulgidus protein (Af1503), the Escherichia coli osmosensor EnvZ(Ec), the E. coli nitrate/nitrite sensor NarX(Ec), and the aspartate chemoreceptor of E. coli (Tar(Ec)). Far-UV CD and NMR spectroscopy were used to monitor the induction of secondary structure upon association with neutral or acidic large unilamellar vesicles (LUVs) and bicelles. We observed significant increases in alpha-helicity within AS1 from NarX(Ec) and Tar(Ec) but not in AS1 from the other proteins. To characterize these interactions further, we determined the solution structure of AS1 from Tar(Ec) associated with acidic bicelles. The bulk of AS1 formed an amphipathic alpha-helix, whereas the N-terminal control cable, the region between TM2 and AS1, remained unstructured. We observed that the conserved prolyl residue found in AS1 of many membrane-adjacent HAMP domains defined the boundary between the unstructured and helical regions. In addition, two positively charged residues that flank the hydrophobic surface of AS1 are thought to facilitate electrostatic interactions with the membrane. We interpret these results within the context of the helix-interaction model for HAMP signaling and propose roles for AS1-membrane interactions during the membrane assembly and transmembrane communication of HAMP-containing receptors.

  • 6.
    Ye, Weihua
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Spånning, Erika
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Unnerståle, Sofia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gotthold, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Glaser, Elzbieta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mäler, Lena
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    NMR investigations of the dual targeting peptide of Thr-tRNA synthetase and its interaction with the mitochondrial Tom20 receptor in Arabidopsis thaliana2012In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 279, no 19, p. 3738-3748Article in journal (Refereed)
    Abstract [en]

    Most mitochondrial proteins are synthesized in the cytosol as precursor proteins containing an N-terminal targeting peptide and are imported into mitochondria through the import machineries, the translocase of the outer mitochondrial membrane (TOM) and the translocase of the inner mitochondrial membrane (TIM). The N-terminal targeting peptide of precursor proteins destined for the mitochondrial matrix is recognized by the Tom20 receptor and plays an important role in the import process. Protein import is usually organelle specific, but several plant proteins are dually targeted into mitochondria and chloroplasts using an ambiguous dual targeting peptide. We present NMR studies of the dual targeting peptide of Thr-tRNA synthetase and its interaction with Tom20 in Arabidopsis thaliana. Our findings show that the targeting peptide is mostly unstructured in buffer, with a propensity to form a-helical structure in one region, S6F27, and a very weak beta-strand propensity for Q34Q38. The a-helical structured region has an amphiphilic character and a f??ff motif, both of which have previously been shown to be important for mitochondrial import. Using NMR we have mapped out two regions in the peptide that are important for Tom20 recognition: one of them, F9V28, overlaps with the amphiphilic region, and the other comprises residues L30Q39. Our results show that the targeting peptide may interact with Tom20 in several ways. Furthermore, our results indicate a weak, dynamic interaction. The results provide for the first time molecular details on the interaction of the Tom20 receptor with a dual targeting peptide. Database The backbone chemical shift assignments for ThrRS-dTP(260) have been deposited with the Biological Magnetic Resonance Bank (BMRB) under the accession code 18248 Structured digital abstract ThrRS-dTP and Tom20-4 bind by nuclear magnetic resonance (View interaction)

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