The ?-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure.

ABSTRACT: Aggregation of ?-synuclein is a defining molecular feature of Parkinson's disease, Lewy body dementia, and multiple systems atrophy. Hereditary mutations in ?-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 ?-synuclein fibril structure is fundamental to ?-synuclein biology. We therefore determined the cryo-electron microscopy (cryo-EM) structure of ?-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 ?-synuclein into a kinetic trap-a shallower, more accessible energy minimum. The E46K mutation apparently unlocks a more stable and pathogenic fibril structure.

SUBMITTER: Boyer DR 

PROVIDER: S-EPMC7035510 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature