8RI9

Late alpha-Synuclein fibril structure from liquid-liquid phase separations.

Summary for 8RI9

• Entry DOI: 10.2210/pdb8ri9/pdb
• EMDB information: 19184
• Descriptor: Alpha-synuclein (1 entity in total)
• Functional Keywords: amyloid, fibril, neurodegeneration, parkinson's disease, protein fibril
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 5
• Total formula weight: 72380.54

Authors

De Simone, A.,Barritt, J.D.,Chen, S.,Cascella, R.,Cecchi, C.,Bigi, A.,Jarvis, J.A.,Chiti, F.,Dobson, C.M.,Fusco, G. (deposition date: 2023-12-18, release date: 2024-03-06, Last modification date: 2024-05-01)

Primary citation

Chen, S.W.,Barritt, J.D.,Cascella, R.,Bigi, A.,Cecchi, C.,Banchelli, M.,Gallo, A.,Jarvis, J.A.,Chiti, F.,Dobson, C.M.,Fusco, G.,De Simone, A.
Structure-Toxicity Relationship in Intermediate Fibrils from alpha-Synuclein Condensates.
J.Am.Chem.Soc., 146:10537-10549, 2024

PubMed Abstract: The aberrant aggregation of α-synuclein (αS) into amyloid fibrils is associated with a range of highly debilitating neurodegenerative conditions, including Parkinson's disease. Although the structural properties of mature amyloids of αS are currently understood, the nature of transient protofilaments and fibrils that appear during αS aggregation remains elusive. Using solid-state nuclear magnetic resonance (ssNMR), cryogenic electron microscopy (cryo-EM), and biophysical methods, we here characterized intermediate amyloid fibrils of αS forming during the aggregation from liquid-like spherical condensates to mature amyloids adopting the structure of pathologically observed aggregates. These transient amyloid intermediates, which induce significant levels of cytotoxicity when incubated with neuronal cells, were found to be stabilized by a small core in an antiparallel β-sheet conformation, with a disordered N-terminal region of the protein remaining available to mediate membrane binding. In contrast, mature amyloids that subsequently appear during the aggregation showed different structural and biological properties, including low levels of cytotoxicity, a rearranged structured core embedding also the N-terminal region, and a reduced propensity to interact with the membrane. The characterization of these two fibrillar forms of αS, and the use of antibodies and designed mutants, enabled us to clarify the role of critical structural elements endowing intermediate amyloid species with the ability to interact with membranes and induce cytotoxicity.

PubMed: 38567991
DOI: 10.1021/jacs.3c14703

Experimental method

ELECTRON MICROSCOPY (3.3 Å)