title: Structure and properties of alpha-synuclein and other amyloids determined at the amino acid level.
abstract: The structure of alpha-synuclein (alpha-syn) amyloid was studied by hydrogen-deuterium exchange by using a fragment separation-MS analysis. The conditions used made it possible to distinguish the exchange of unprotected and protected amide hydrogens and to define the order/disorder boundaries at close to amino acid resolution. The soluble alpha-syn monomer exchanges its amide hydrogens with water hydrogens at random coil rates, consistent with its natively unstructured condition. In assembled amyloid, long N-terminal and C-terminal segments remain unprotected (residues 1- approximately 38 and 102-140), although the N-terminal segment shows some heterogeneity. A continuous middle segment (residues approximately 39-101) is strongly protected by systematically H-bonded cross-beta structure. This segment is much too long to fit the amyloid ribbon width, but non-H-bonded amides expected for direction-changing loops are not apparent. These results and other known constraints specify that alpha-syn amyloid adopts a chain fold like that suggested before for amyloid-beta [Petkova et al. (2002) Proc. Natl. Acad Sci. USA 99, 16742-16747] but with a short, H-bonded interlamina turn. More generally, we suggest that the prevalence of accidental amyloid formation derives mainly from the exceptional ability of the main chain in a structurally relaxed beta-conformation to adapt to and energy-minimize side-chain mismatching. Seeding specificity, strain variability, and species barriers then arise because newly added parallel in-register chains must faithfully reproduce the same set of adaptations.
authors.affiliation: The Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Charyl
authors.initials: C
authors.lastname: Del Mar
authors.forename: Eric A
authors.initials: EA
authors.lastname: Greenbaum
authors.forename: Leland
authors.initials: L
authors.lastname: Mayne
authors.forename: S Walter
authors.initials: SW
authors.lastname: Englander
authors.forename: Virgil L
authors.initials: VL
authors.lastname: Woods
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D002942:Circular Dichroism; D006860:Hydrogen Bonding; D013058:Mass Spectrometry; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D000682:Amyloid; D051844:alpha-Synuclein