Interaction
of Alpha-Synuclein and Its Mutants with
Rigid Lipid Vesicle Mimics of Varying Surface Curvature
Posted on 2020-07-22 - 14:06
Abnormal
aggregation of alpha-synuclein (α-syn), an intrinsically
disordered neuronal protein, is strongly implicated in the development
of Parkinson’s disease. Efforts to better understand α-syn’s
native function and its pathogenic role in neurodegeneration have
revealed that the protein interacts with anionic lipid vesicles via adoption of an amphipathic α-helical structure;
however, the ability of α-syn to remodel lipid membranes has
made it difficult to decipher the role of vesicle surface curvature
in protein binding behavior. In this study, sodium dodecyl sulfate
(SDS)-coated gold nanoparticles (AuNPs), which mimic bilayer vesicle
architecture, were synthesized in order to conduct a systematic investigation
into the binding interaction of α-syn and two of its mutants
(A30P and E46K) with rigid lipid vesicle mimics of defined surface
curvature. By incorporating a rigid AuNP core (∼10–100
nm), the ability of α-syn to remodel the vesicle mimics was
removed and their surface curvature could be fixed. Proteomics studies
showed that, upon binding of free α-syn to the surface of SDS-AuNPs,
the N-terminus of α-syn became less solvent accessible, whereas
its C-terminus became more accessible. Interestingly, α-syn’s
non-amyloid-β component (NAC) region also exhibited increased
solvent accessibility, suggesting that α-syn bound to rigid
vesicle-like structures could possess heightened aggregation propensity
and therefore pathogenicity. Additionally, both the A30P and E46K
mutations were found to adopt distinct binding modes on the mimics’
surface. In contrast with previous reports, similar binding affinities
were observed for WT, A30P, and E46K α-syn toward SDS-AuNPs
of all sizes, indicating the potential importance of vesicle deformability
in determining α-syn binding behavior.
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McClain, Sophia
M.; Ojoawo, Adedolapo M.; Lin, Wayne; Rienstra, Chad M.; Murphy, Catherine J. (2020). Interaction
of Alpha-Synuclein and Its Mutants with
Rigid Lipid Vesicle Mimics of Varying Surface Curvature. ACS Publications. Collection. https://doi.org/10.1021/acsnano.0c03420