Structure and properties of α-synuclein and other amyloids determined at the amino acid level

C Del Mar, EA Greenbaum, L Mayne… - Proceedings of the …, 2005 - National Acad Sciences
C Del Mar, EA Greenbaum, L Mayne, SW Englander, VL Woods Jr
Proceedings of the National Academy of Sciences, 2005National Acad Sciences
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 …
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.
National Acad Sciences