Structure and Properties of α-Synuclein and Other Amyloids Determined at the Amino Acid Level

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 43; pp. 15477 - 15482
• Main Authors: Del Mar, Charyl, Greenbaum, Eric A., Mayne, Leland, Englander, S. Walter, Woods, Virgil L.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.10.2005; National Acad Sciences
• Subjects: alpha-Synuclein - chemistry; Amides; Amino acids; Amyloid - chemistry; Amyloids; Biochemistry; Biological Sciences; Biophysics; Circular Dichroism; Crystal structure; Hydrogen; Hydrogen Bonding; Hydrogen bonds; Mass Spectrometry; Molecules; Monomers; Proteins; Seeding; Solvents
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0507405102

The structure of α-synuclein (α-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 α-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-≈38 and 102-140), although the N-terminal segment shows some heterogeneity. A continuous middle segment (residues ≈39-101) is strongly protected by systematically H-bonded cross-β 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 α-syn amyloid adopts a chain fold like that suggested before for amyloid-β [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 β-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.