6PEO

Cryo-EM structure of alpha-synuclein H50Q Narrow Fibril

Summary for 6PEO

• Entry DOI: 10.2210/pdb6peo/pdb
• EMDB information: 20328
• Descriptor: Alpha-synuclein (1 entity in total)
• Functional Keywords: alpha-synuclein, amyloid, h50q, hereditary mutation, fibril, protein fibril
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 5
• Total formula weight: 72330.46

Authors

Boyer, D.R.,Li, B.,Sawaya, M.R.,Jiang, L.,Eisenberg, D.S. (deposition date: 2019-06-20, release date: 2019-11-27, Last modification date: 2025-06-04)

Primary citation

Boyer, D.R.,Li, B.,Sun, C.,Fan, W.,Sawaya, M.R.,Jiang, L.,Eisenberg, D.S.
Structures of fibrils formed by alpha-synuclein hereditary disease mutant H50Q reveal new polymorphs.
Nat.Struct.Mol.Biol., 26:1044-1052, 2019

PubMed Abstract: Deposits of amyloid fibrils of α-synuclein are the histological hallmarks of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, with hereditary mutations in α-synuclein linked to the first two of these conditions. Seeing the changes to the structures of amyloid fibrils bearing these mutations may help to understand these diseases. To this end, we determined the cryo-EM structures of α-synuclein fibrils containing the H50Q hereditary mutation. We find that the H50Q mutation results in two previously unobserved polymorphs of α-synuclein: narrow and wide fibrils, formed from either one or two protofilaments, respectively. These structures recapitulate conserved features of the wild-type fold but reveal new structural elements, including a previously unobserved hydrogen-bond network and surprising new protofilament arrangements. The structures of the H50Q polymorphs help to rationalize the faster aggregation kinetics, higher seeding capacity in biosensor cells and greater cytotoxicity that we observe for H50Q compared to wild-type α-synuclein.

PubMed: 31695184
DOI: 10.1038/s41594-019-0322-y

Experimental method

ELECTRON MICROSCOPY (3.3 Å)