Structure and properties of alpha-synuclein and other amyloids determined at the amino acid level.
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.
Del Mar
Charyl
C
The Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Greenbaum
Eric A
EA
Mayne
Leland
L
Englander
S Walter
SW
Woods
Virgil L
VL
D000682:Amyloid / Q000737:chemistry*; D002942:Circular Dichroism; D006860:Hydrogen Bonding; D013058:Mass Spectrometry; D051844:alpha-Synuclein / Q000737:chemistry*
D000682:Amyloid; D051844:alpha-Synuclein