6UFR
Structure of recombinantly assembled E46K alpha-synuclein fibrils
Summary for 6UFR
| Entry DOI | 10.2210/pdb6ufr/pdb |
| EMDB information | 20759 |
| Descriptor | Alpha-synuclein (2 entities in total) |
| Functional Keywords | alpha-synuclein, amyloid, fibril, e46k, hereditary mutations, parkinson's disease, lewy body dementia, protein fibril |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 10 |
| Total formula weight | 144761.75 |
| Authors | Eisenberg, D.S.,Boyer, D.R.,Sawaya, M.R.,Li, B.,Jiang, L. (deposition date: 2019-09-24, release date: 2020-02-19, Last modification date: 2025-05-28) |
| Primary citation | Boyer, D.R.,Li, B.,Sun, C.,Fan, W.,Zhou, K.,Hughes, M.P.,Sawaya, M.R.,Jiang, L.,Eisenberg, D.S. The alpha-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure. Proc.Natl.Acad.Sci.USA, 117:3592-3602, 2020 Cited by PubMed Abstract: Aggregation of α-synuclein is a defining molecular feature of Parkinson's disease, Lewy body dementia, and multiple systems atrophy. Hereditary mutations in α-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 α-synuclein fibril structure is fundamental to α-synuclein biology. We therefore determined the cryo-electron microscopy (cryo-EM) structure of α-synuclein fibrils containing the hereditary E46K mutation. The 2.5-Å 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 α-synuclein into a kinetic trap-a shallower, more accessible energy minimum. The E46K mutation apparently unlocks a more stable and pathogenic fibril structure. PubMed: 32015135DOI: 10.1073/pnas.1917914117 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.5 Å) |
Structure validation
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