Maqola

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

David R. BoyerDepartment of Biological Chemistry, University of California, Los Angeles, CA 90095;Binsen LiDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;Chuanqi SunDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;Weijia FanDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;Kang ZhouCalifornia NanoSystems Institute, University of California, Los Angeles, CA 90095Michael P. HughesDepartment of Biological Chemistry, University of California, Los Angeles, CA 90095;M.R. SawayaDepartment of Biological Chemistry, University of California, Los Angeles, CA 90095;Lin JiangDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;David EisenbergDepartment of Biological Chemistry, University of California, Los Angeles, CA 90095;

2020en

ABI

Annotatsiya

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.

Hali tarjima qilinmagan

Identifikatorlar

DOI: 10.1073/pnas.1917914117

Iqtiboslar va manbalar

2 ta iqtibos0 ta foydalanilgan manba

Koʻrsatkichlar — AkademScholar