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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

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

Boyer David R DR Li Binsen B Sun Chuanqi C Fan Weijia W Zhou Kang K Hughes Michael P MP Sawaya Michael R MR Jiang Lin L Eisenberg David S DS

Proceedings of the National Academy of Sciences of the United States of America 20200203 7

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 f ...[more]

PMID: 32015135

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Project description:The E46K genetic missense mutation of the wild-type ?-synuclein protein was recently identified in a family of Spanish origin with hereditary Parkinson's disease. Detailed understanding of the structures of the monomeric E46K mutant-type ?-synuclein protein as well as the impact of the E46K missense mutation on the conformations and free energy landscapes of the wild-type ?-synuclein are required for gaining insights into the pathogenic mechanism of Parkinson's disease. In this study, we use extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations to assess the secondary and tertiary structural properties as well as the conformational preferences of the monomeric wild-type and E46K mutant-type ?-synuclein proteins in an aqueous solution environment. We also present the residual secondary structure component conversion stabilities with dynamics using a theoretical strategy, which we most recently developed. To the best of our knowledge, this study presents the first detailed comparison of the structural and thermodynamic properties of the wild-type and E46K mutant-type ?-synuclein proteins in an aqueous solution environment at the atomic level with dynamics. We find that the E46K mutation results not only in local but also in long-range changes in the structural properties of the wild-type ?-synuclein protein. The mutation site shows a significant decrease in helical content as well as a large increase in ?-sheet structure formation upon E46K mutation. In addition, the ?-sheet content of the C-terminal region increases significantly in the E46K mutant-type ?S in comparison to the wild-type ?S. Our theoretical strategy developed to assess the thermodynamic preference of secondary structure transitions indicates that this shift in secondary structure is the result of a decrease in the thermodynamic preference of turn to helix conversions while the coil to ?-sheet preference increases for these residues. Long-range intramolecular protein interactions of the C-terminal with the N-terminal and NAC regions increase upon E46K mutation, resulting in more compact structures for the E46K mutant-type rather than wild-type ?S. However, the E46K mutant-type ?S structures are less stable than the wild-type ?S. Overall, our results show that the E46K mutant-type ?S has a higher propensity to aggregate than the wild-type ?S and that the N-terminal and C-terminal regions are reactive toward fibrillization and aggregation upon E46K mutation and we explain the associated reasons based on the structural properties herein. Small molecules or drugs that can block the specific residues forming abundant ?-sheet structure, which we report here, might help to reduce the reactivity of these intrinsically disordered fibrillogenic proteins toward aggregation and their toxicity.

Dataset Information

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

Publications

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

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