The Alpha-Synuclein Fibril Fold - Comparing Models from Electron Paramagnetic Resonance and NMR

Amyloid fibrils and plaques are hallmarks of neurodegenerative diseases. In Parkinson's disease, plaques (Lewy bodies) consist predominantly of the α-synuclein (αS) protein. To understand aggregation and elucidate the role of mutants in the disease, the molecular architecture of αS fibrils needs to be known. By double electron-electron paramagnetic resonance (DEER), nm-distance constraints can be determined. This is done by DEER on fibrils of doubly spin-labeled αS-variants, diamagnetically diluted with wild-type αS to suppress intermolecular interactions. Intramolecular distances in three pairs (56/69, 56/90 and 69/90) are reported. An approach to derive a model for the fibril-fold from sparse distance data assuming parallel β-sheets is described. Using the DEER distances as input, a model was derived with three strands, comprising residues 56 to 90, in which the strands consist of eight to twelve residues each. Details are described in[1], where also the viability of such a simple model is discussed.Comparison to structural models in the literature given in[1] is augmented in the present contribution by the discussion of the recently published NMR structure of αS fibrils.[2] This structure enables us to compare our constraints directly with the NMR-derived structure, using the MMM model for spin-label attachment.[3][1] Hashemi Shabestari et al. Appl Magn Reson 46, 369 (2015) DOI 10.1007/s00723-014-0622-7[2] Tuttle et al. Nat Struct Mol Biol. 23, 409 (2016)[3] Polyhach et al. Physical Chemistry Chemical Physics 13 2356 (2011)