The structural heterogeneity of α-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds.

Fluorescence Resonance Energy Transfer Humans Molecular Dynamics Simulation alpha-Synuclein / chemistry
conformational ensemble discrete molecular dynamics simulations intrinsically disordered protein neurodegenerative diseases α-synuclein

Journal

Structure (London, England : 1993)
ISSN: 1878-4186
Titre abrégé: Structure
Pays: United States
ID NLM: 101087697

Informations de publication

Date de publication:
02 09 2021
Historique:
received: 18 01 2021
revised: 12 03 2021
accepted: 30 04 2021
pubmed: 21 5 2021
medline: 17 3 2022
entrez: 20 5 2021
Statut: ppublish

Résumé

α-Synuclein plays an important role in synaptic functions by interacting with synaptic vesicle membrane, while its oligomers and fibrils are associated with several neurodegenerative diseases. The specific monomer structures that promote its membrane binding and self-association remain elusive due to its transient nature as an intrinsically disordered protein. Here, we use inter-dye distance distributions from bulk time-resolved Förster resonance energy transfer as restraints in discrete molecular dynamics simulations to map the conformational space of the α-synuclein monomer. We further confirm the generated conformational ensemble in orthogonal experiments utilizing far-UV circular dichroism and cross-linking mass spectrometry. Single-molecule protein-induced fluorescence enhancement measurements show that within this conformational ensemble, some of the conformations of α-synuclein are surprisingly stable, exhibiting conformational transitions slower than milliseconds. Our comprehensive analysis of the conformational ensemble reveals essential structural properties and potential conformations that promote its various functions in membrane interaction or oligomer and fibril formation.

Identifiants

DOI: 10.1016/j.str.2021.05.002 PMID: 34015255 PMC: PMC8419013
pubmed: 34015255
pii: S0969-2126(21)00160-X
doi: 10.1016/j.str.2021.05.002
pmc: PMC8419013
mid: NIHMS1702938
pii:
doi:

Substances chimiques

alpha-Synuclein 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1048-1064.e6

Subventions

Organisme : NIGMS NIH HHS
ID : R01 GM130942
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM134864
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002014
Pays : United States

Informations de copyright

Copyright © 2021 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

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Auteurs

Jiaxing Chen (J)

Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA.

Sofia Zaer (S)

Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Faculty of Mathematics & Science, The Edmond J. Safra Campus, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.

Paz Drori (P)

Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Faculty of Mathematics & Science, The Edmond J. Safra Campus, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.

Joanna Zamel (J)

Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Faculty of Mathematics & Science, The Edmond J. Safra Campus, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.

Khalil Joron (K)

Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Faculty of Mathematics & Science, The Edmond J. Safra Campus, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.

Nir Kalisman (N)

Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Faculty of Mathematics & Science, The Edmond J. Safra Campus, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.

Eitan Lerner (E)

Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Faculty of Mathematics & Science, The Edmond J. Safra Campus, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel; The Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel. Electronic address: eitan.lerner@mail.huji.ac.il.

Nikolay V Dokholyan (NV)

Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA; Department of Biochemistry & Molecular Biology, Penn State College of Medicine, Hershey, PA 17033, USA; Departments of Chemistry and Biomedical Engineering, Pennsylvania State University, University Park, PA 16802, USA. Electronic address: dokh@psu.edu.

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Classifications MeSH

questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Transfert d'énergie par résonance de fluorescence › The structural heterogeneity of α-synuclein is...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The structural heterogeneity of α-synuclein is...
questionsmedicales.fr › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de dynamique moléculaire › The structural heterogeneity of α-synuclein is...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines associées à la maladie de Parkinson › alpha-Synucléine › The structural heterogeneity of α-synuclein is...