6CU8

Alpha Synuclein fibril formed by full length protein - Twister Polymorph

Summary for 6CU8

• Entry DOI: 10.2210/pdb6cu8/pdb
• Related: 6CU7
• EMDB information: 7619
• Descriptor: Alpha-synuclein (1 entity in total)
• Functional Keywords: parkinson's disease, synucleinopathy, amyloid aggregation, fibril polymorphism, protein fibril
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 10
• Total formula weight: 144761.08

Authors

Li, B.,Hatami, A.,Ge, P.,Murray, K.A.,Sheth, P.,Zhang, M.,Nair, G.,Sawaya, M.R.,Zhu, C.,Broad, M.,Shin, W.S.,Ye, S.,John, V.,Eisenberg, D.S.,Zhou, Z.H.,Jiang, L. (deposition date: 2018-03-23, release date: 2018-09-12, Last modification date: 2024-03-13)

Primary citation

Li, B.,Ge, P.,Murray, K.A.,Sheth, P.,Zhang, M.,Nair, G.,Sawaya, M.R.,Shin, W.S.,Boyer, D.R.,Ye, S.,Eisenberg, D.S.,Zhou, Z.H.,Jiang, L.
Cryo-EM of full-length alpha-synuclein reveals fibril polymorphs with a common structural kernel.
Nat Commun, 9:3609-3609, 2018

PubMed Abstract: α-Synuclein (aSyn) fibrillar polymorphs have distinct in vitro and in vivo seeding activities, contributing differently to synucleinopathies. Despite numerous prior attempts, how polymorphic aSyn fibrils differ in atomic structure remains elusive. Here, we present fibril polymorphs from the full-length recombinant human aSyn and their seeding capacity and cytotoxicity in vitro. By cryo-electron microscopy helical reconstruction, we determine the structures of the two predominant species, a rod and a twister, both at 3.7 Å resolution. Our atomic models reveal that both polymorphs share a kernel structure of a bent β-arch, but differ in their inter-protofilament interfaces. Thus, different packing of the same kernel structure gives rise to distinct fibril polymorphs. Analyses of disease-related familial mutations suggest their potential contribution to the pathogenesis of synucleinopathies by altering population distribution of the fibril polymorphs. Drug design targeting amyloid fibrils in neurodegenerative diseases should consider the formation and distribution of concurrent fibril polymorphs.

PubMed: 30190461
DOI: 10.1038/s41467-018-05971-2

Experimental method

ELECTRON MICROSCOPY (3.6 Å)