6A6B

cryo-em structure of alpha-synuclein fiber

Summary for 6A6B

• Entry DOI: 10.2210/pdb6a6b/pdb
• EMDB information: 6988
• Descriptor: Alpha-synuclein (1 entity in total)
• Functional Keywords: alpha-syn fiber, parkinson disease, protein fibril
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 12
• Total formula weight: 75013.16

Authors

Li, Y.W.,Zhao, C.Y.,Luo, F.,Liu, Z.,Gui, X.,Luo, Z.,Zhang, X.,Li, D.,Liu, C.,Li, X. (deposition date: 2018-06-27, release date: 2018-07-11, Last modification date: 2024-03-27)

Primary citation

Li, Y.,Zhao, C.,Luo, F.,Liu, Z.,Gui, X.,Luo, Z.,Zhang, X.,Li, D.,Liu, C.,Li, X.
Amyloid fibril structure of alpha-synuclein determined by cryo-electron microscopy
Cell Res., 28:897-903, 2018

PubMed Abstract: α-Synuclein (α-syn) amyloid fibrils are the major component of Lewy bodies, which are the pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. High-resolution structure of α-syn fibril is important for understanding its assembly and pathological mechanism. Here, we determined a fibril structure of full-length α-syn (1-140) at the resolution of 3.07 Å by cryo-electron microscopy (cryo-EM). The fibrils are cytotoxic, and transmissible to induce endogenous α-syn aggregation in primary neurons. Based on the reconstructed cryo-EM density map, we were able to unambiguously build the fibril structure comprising residues 37-99. The α-syn amyloid fibril structure shows two protofilaments intertwining along an approximate 2 screw axis into a left-handed helix. Each protofilament features a Greek key-like topology. Remarkably, five out of the six early-onset PD familial mutations are located at the dimer interface of the fibril (H50Q, G51D, and A53T/E) or involved in the stabilization of the protofilament (E46K). Furthermore, these PD mutations lead to the formation of fibrils with polymorphic structures distinct from that of the wild-type. Our study provides molecular insight into the fibrillar assembly of α-syn at the atomic level and sheds light on the molecular pathogenesis caused by familial PD mutations of α-syn.

PubMed: 30065316
DOI: 10.1038/s41422-018-0075-x

Experimental method

ELECTRON MICROSCOPY (3.07 Å)