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Structural insights from lipid-bilayer nanodiscs link ?-Synuclein membrane-binding modes to amyloid fibril formation.

ABSTRACT: The protein ?-Synuclein (?S) is linked to Parkinson's disease through its abnormal aggregation, which is thought to involve cytosolic and membrane-bound forms of ?S. Following previous studies using micelles and vesicles, we present a comprehensive study of ?S interaction with phospholipid bilayer nanodiscs. Using a combination of NMR-spectroscopic, biophysical, and computational methods, we structurally and kinetically characterize ?S interaction with different membrane discs in a quantitative and site-resolved way. We obtain global and residue-specific ?S membrane affinities, and determine modulations of ?S membrane binding due to ?S acetylation, membrane plasticity, lipid charge density, and accessible membrane surface area, as well as the consequences of the different binding modes for ?S amyloid fibril formation. Our results establish a structural and kinetic link between the observed dissimilar binding modes and either aggregation-inhibiting properties, largely unperturbed aggregation, or accelerated aggregation due to membrane-assisted fibril nucleation.

SUBMITTER: Viennet T

PROVIDER: S-EPMC6123806 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Structural insights from lipid-bilayer nanodiscs link α-Synuclein membrane-binding modes to amyloid fibril formation.

Viennet Thibault T Wördehoff Michael M MM Uluca Boran B Poojari Chetan C Shaykhalishahi Hamed H Willbold Dieter D Strodel Birgit B Heise Henrike H Buell Alexander K AK Hoyer Wolfgang W Etzkorn Manuel M

Communications biology 20180503

The protein α-Synuclein (αS) is linked to Parkinson's disease through its abnormal aggregation, which is thought to involve cytosolic and membrane-bound forms of αS. Following previous studies using micelles and vesicles, we present a comprehensive study of αS interaction with phospholipid bilayer nanodiscs. Using a combination of NMR-spectroscopic, biophysical, and computational methods, we structurally and kinetically characterize αS interaction with different membrane discs in a quantitative ...[more]

PMID: 30271927

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Project description:Lipid nanodiscs are small synthetic lipid bilayer structures that are stabilized in solution by special circumscribing (or scaffolding) proteins or polymers. Because they create native-like environments for transmembrane proteins, lipid nanodiscs have become a powerful tool for structural determination of this class of systems when combined with cryo-electron microscopy or nuclear magnetic resonance. The elastic properties of lipid bilayers determine how the lipid environment responds to membrane protein perturbations, and how the lipid in turn modifies the conformational state of the embedded protein. However, despite the abundant use of nanodiscs in determining membrane protein structure, the elastic material properties of even pure lipid nanodiscs (i.e., without embedded proteins) have not yet been quantitatively investigated. A major hurdle is due to the inherently nonlocal treatment of the elastic properties of lipid systems implemented by most existing methods, both experimental and computational. In addition, these methods are best suited for very large "infinite" size lipidic assemblies, or ones that contain periodicity, in the case of simulations. We have previously described a computational analysis of molecular dynamics simulations designed to overcome these limitations, so it allows quantification of the bending rigidity (KC) and tilt modulus (κt) on a local scale even for finite, nonperiodic systems, such as lipid nanodiscs. Here we use this computational approach to extract values of KC and κt for a set of lipid nanodisc systems that vary in size and lipid composition. We find that the material properties of lipid nanodiscs are different from those of infinite bilayers of corresponding lipid composition, highlighting the effect of nanodisc confinement. Nanodiscs tend to show higher stiffness than their corresponding macroscopic bilayers, and moreover, their material properties vary spatially within them. For small-size MSP1 nanodiscs, the stiffness decreases radially, from a value that is larger in their center than the moduli of the corresponding bilayers by a factor of ∼2-3. The larger nanodiscs (MSP1E3D1 and MSP2N2) show milder spatial changes of moduli that are composition dependent and can be maximal in the center or at some distance from it. These trends in moduli correlate with spatially varying structural properties, including the area per lipid and the nanodisc thickness. Finally, as has previously been reported, nanodiscs tend to show deformations from perfectly flat circular geometries to varying degrees, depending on size and lipid composition. The modulations of lipid elastic properties that we find should be carefully considered when making structural and functional inferences concerning embedded proteins.

Dataset Information

Structural insights from lipid-bilayer nanodiscs link ?-Synuclein membrane-binding modes to amyloid fibril formation.

Publications

Structural insights from lipid-bilayer nanodiscs link α-Synuclein membrane-binding modes to amyloid fibril formation.

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