Structure and dynamics of the extended-helix state of alpha-synuclein: Intrinsic lability of the linker region. Academic Article uri icon

Overview

abstract

  • The Parkinson's protein alpha-synuclein binds to synaptic vesicles in vivo and adopts a highly extended helical conformation when binding to lipid vesicles in vitro. High-resolution structural analysis of alpha-synuclein bound to small lipid or detergent micelles revealed two helices connected by a non-helical linker, but corresponding studies of the vesicle-bound extended-helix state are hampered by the size and heterogeneity of the protein-vesicle complex. Here we employ fluorinated alcohols (FAs) to induce a highly helical aggregation-resistant state of alpha-synuclein in solution that resembles the vesicle-bound extended-helix state but is amenable to characterization using high-resolution solution-state NMR. Analysis of chemical shift, NOE, coupling constant, PRE and relaxation measurements shows that the lipid-binding domain of alpha-synuclein in FA solutions indeed adopts a single continuous helix and that the ends of this helix do not come into detectable proximity to each other. The helix is well ordered in the center, but features an increase in fast internal motions suggestive of helix fraying approaching the termini. The central region of the helix exhibits slower time scale motions that likely result from flexing of the highly anisotropic structure. Importantly, weak or missing short- and intermediate-range NOEs in the region corresponding to the non-helical linker of micelle-bound alpha-synuclein indicate that the helical structure in this region of the protein is intrinsically unstable. This suggests that conversion of alpha-synuclein from the extended-helix to the broken-helix state represents a functionally relevant structural transition.

publication date

  • July 1, 2018

Research

keywords

  • Alcohols
  • alpha-Synuclein

Identity

PubMed Central ID

  • PMC6032355

Scopus Document Identifier

  • 85049552923

Digital Object Identifier (DOI)

  • 10.1101/173724

PubMed ID

  • 29663556

Additional Document Info

volume

  • 27

issue

  • 7