The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure
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.
- Publication Date:
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1597118
- Grant/Contract Number:
- FC02-02ER63421
- Resource Type:
- Published Article
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Volume: 117 Journal Issue: 7; Journal ID: ISSN 0027-8424
- Publisher:
- Proceedings of the National Academy of Sciences
- Country of Publication:
- United States
- Language:
- English
Citation Formats
Boyer, David R., Li, Binsen, Sun, Chuanqi, Fan, Weijia, Zhou, Kang, Hughes, Michael P., Sawaya, Michael R., Jiang, Lin, and Eisenberg, David S. The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure. United States: N. p., 2020.
Web. doi:10.1073/pnas.1917914117.
Boyer, David R., Li, Binsen, Sun, Chuanqi, Fan, Weijia, Zhou, Kang, Hughes, Michael P., Sawaya, Michael R., Jiang, Lin, & Eisenberg, David S. The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure. United States. doi:10.1073/pnas.1917914117.
Boyer, David R., Li, Binsen, Sun, Chuanqi, Fan, Weijia, Zhou, Kang, Hughes, Michael P., Sawaya, Michael R., Jiang, Lin, and Eisenberg, David S. Mon .
"The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure". United States. doi:10.1073/pnas.1917914117.
@article{osti_1597118,
title = {The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure},
author = {Boyer, David R. and Li, Binsen and Sun, Chuanqi and Fan, Weijia and Zhou, Kang and Hughes, Michael P. and Sawaya, Michael R. and Jiang, Lin and Eisenberg, David S.},
abstractNote = {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.},
doi = {10.1073/pnas.1917914117},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 7,
volume = 117,
place = {United States},
year = {2020},
month = {2}
}
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DOI: 10.1073/pnas.1917914117
DOI: 10.1073/pnas.1917914117
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