Title: 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.

Authors:

Boyer, David R.  ^[1];

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Li, Binsen ^[2]; Sun, Chuanqi ^[2]; Fan, Weijia ^[2]; Zhou, Kang ^[3]; Hughes, Michael P. ^[1]; Sawaya, Michael R. ^[1]; Jiang, Lin ^[2]; Eisenberg, David S. ^[1]

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+ Show Author Affiliations

1. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095,, Department of Biological Chemistry, University of California, Los Angeles, CA 90095,, Department of Energy Institute, University of California, Los Angeles, CA 90095,, Molecular Biology Institute, University of California, Los Angeles, CA 90095,, Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095,
2. Molecular Biology Institute, University of California, Los Angeles, CA 90095,, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095,
3. California NanoSystems Institute, University of California, Los Angeles, CA 90095

Publication Date:

2020-02-03

Research Org.:

Univ. of California, Los Angeles, CA (United States)

Sponsoring Org.:

USDOE Office of Science (SC)

OSTI Identifier:

1597118

Alternate Identifier(s):

OSTI ID: 1799617

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

Subject:

59 BASIC BIOLOGICAL SCIENCES; α-synuclein; Parkinson’s disease; Lewy body dementia; cryo-EM; hereditary mutations