Modeling the effects of phosphorylation on phase separation of the FUS low-complexity domain.

Phosphorylation Protein Domains Molecular Dynamics Simulation RNA-Binding Proteins / metabolism RNA-Binding Protein FUS / chemistry

Journal

Biophysical journal
ISSN: 1542-0086
Titre abrégé: Biophys J
Pays: United States
ID NLM: 0370626

Informations de publication

Date de publication:
11 07 2023
Historique:
received: 30 12 2022
revised: 13 05 2023
accepted: 18 05 2023
pmc-release: 11 07 2024
medline: 14 7 2023
pubmed: 22 5 2023
entrez: 22 5 2023
Statut: ppublish

Résumé

Aggregation of the RNA-binding protein fused in sarcoma (FUS) is a hallmark of neurodegenerative diseases. Phosphorylation of Ser/Thr in the FUS low-complexity domain (FUS-LC) may regulate phase separation of FUS and prevent pathological aggregation in cells. However, many details of this process remain elusive to date. In this work, we systematically investigated the phosphorylation of FUS-LC and the underlying molecular mechanism by molecular dynamics (MD) simulations and free energy calculations. The results clearly show that phosphorylation can destroy the fibril core structure of FUS-LC by breaking interchain interactions, particularly contacts involving residues like Tyr, Ser, and Gln. Among the six phosphorylation sites, Ser61 and Ser84 may have more important effects on the stability of the fibril core. Our study reveals structural and dynamic details of FUS-LC phase separation modulated by phosphorylation.

Identifiants

DOI: 10.1016/j.bpj.2023.05.018 PMID: 37211763 PMC: PMC10397571
pubmed: 37211763
pii: S0006-3495(23)00330-2
doi: 10.1016/j.bpj.2023.05.018
pmc: PMC10397571
pii:
doi:

Substances chimiques

RNA-Binding Proteins 0
RNA-Binding Protein FUS 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2636-2645

Informations de copyright

Copyright © 2023 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare that they have no competing interests.

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Auteurs

Mingwei Li (M)

MOE Key Laboratory for Cellular Dynamics and Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, P.R. China.

Guanglin Chen (G)

Department of Physics, University of Science and Technology of China, Hefei, Anhui, P.R. China.

Zhiyong Zhang (Z)

MOE Key Laboratory for Cellular Dynamics and Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, P.R. China; Department of Physics, University of Science and Technology of China, Hefei, Anhui, P.R. China. Electronic address: zzyzhang@ustc.edu.cn.

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Classifications MeSH

questionsmedicales.fr › Métabolisme › Phosphorylation › Modeling the effects of phosphorylation on...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Structure tertiaire des protéines › Domaines protéiques › Modeling the effects of phosphorylation on...
questionsmedicales.fr › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de dynamique moléculaire › Modeling the effects of phosphorylation on...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines de liaison à l'ARN › Modeling the effects of phosphorylation on...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines de liaison à l'ARN › Protéines à motif de reconnaissance de l'ARN › Ribonucléoprotéines nucléaires hétérogènes › Protéine FUS de liaison à l'ARN › Modeling the effects of phosphorylation on...