期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 7, 页码 3592-3602出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1917914117
关键词
alpha-synuclein; Parkinson's disease; Lewy body dementia; cryo-EM; hereditary mutations
资金
- NIH [1S10RR23057, 1S10OD018111, AG 060149, AG 054022, AG061847]
- NSF [DBI-1338135]
- California NanoSystems Institute at the University of California, Los Angeles
- Department of Energy [DE-FC02-02ER63421]
- National Science Foundation
Aggregation of a-synuclein is a defining molecular feature of Parkinson's disease, Lewy body dementia, and multiple systems atrophy. Hereditary mutations in a-synuclein are linked to both Parkinson's disease and Lewy body dementia; in particular, patients bearing the E46K disease mutation manifest a clinical picture of parkinsonism and Lewy body dementia, and E46K creates more pathogenic fibrils in vitro. Understanding the effect of these hereditary mutations on a-synuclein fibril structure is fundamental to a-synuclein biology. We therefore determined the cryo-electron microscopy (cryo-EM) structure of a-synuclein fibrils containing the hereditary E46K mutation. The 2.5-A structure reveals a symmetric double protofilament in which the molecules adopt a vastly rearranged, lower energy fold compared to wild-type fibrils. We propose that the E46K misfolding pathway avoids electrostatic repulsion between K46 and K80, a residue pair which form the E46-K80 salt bridge in the wild-type fibril structure. We hypothesize that, under our conditions, the wild-type fold does not reach this deeper energy well of the E46K fold because the E46-K80 salt bridge diverts a-synuclein into a kinetic trap-a shallower, more accessible energy minimum. The E46K mutation apparently unlocks a more stable and pathogenic fibril structure.
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