Thermodynamic coupling of the tandem RRM domains of hnRNP A1 underlie its pleiotropic RNA binding functions

Jeffrey D Levengood; Davit Potoyan; Srinivasa Penumutchu; Abhishek Kumar; Qianzi Zhou; Yiqing Wang; Alexandar L Hansen; Sebla Kutluay; Julien Roche; Blanton S Tolbert

doi:10.1126/sciadv.adk6580

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Thermodynamic coupling of the tandem RRM domains of hnRNP A1 underlie its pleiotropic RNA binding functions

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Thermodynamic coupling of the tandem RRM domains of hnRNP A1 underlie its pleiotropic RNA binding functions

Jeffrey D Levengood, Davit Potoyan, Srinivasa Penumutchu, Abhishek Kumar, Qianzi Zhou, Yiqing Wang, Alexandar L Hansen, Sebla Kutluay, Julien Roche et Blanton S Tolbert

Science advances, Vol.10(28), p.eadk6580

12/07/2024

DOI: https://doi.org/10.1126/sciadv.adk6580

PMID: 38985864

Résumé

Allosteric Regulation

Heterogeneous Nuclear Ribonucleoprotein A1 - chemistry

Heterogeneous Nuclear Ribonucleoprotein A1 - genetics

Heterogeneous Nuclear Ribonucleoprotein A1 - metabolism

Humans

Models, Molecular

Mutation

Protein Binding

Protein Domains

Protein Stability

RNA - chemistry

RNA - genetics

RNA - metabolism

RNA Recognition Motif

Thermodynamics

The functional properties of RNA binding proteins (RBPs) require allosteric regulation through interdomain communication. Despite the importance of allostery to biological regulation, only a few studies have been conducted to describe the biophysical nature by which interdomain communication manifests in RBPs. Here, we show for hnRNP A1 that interdomain communication is vital for the unique stability of its amino-terminal domain, which consists of two RNA recognition motifs (RRMs). These RRMs exhibit drastically different stability under pressure. RRM2 unfolds as an individual domain but remains stable when appended to RRM1. Variants that disrupt interdomain communication between the tandem RRMs show a significant decrease in stability. Carrying these mutations over to the full-length protein for in vivo experiments revealed that the mutations affected the ability of the disordered carboxyl-terminal domain to engage in protein-protein interactions and influenced the protein's RNA binding capacity. Collectively, this work reveals that thermodynamic coupling between the tandem RRMs of hnRNP A1 accounts for its allosteric regulatory functions.

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Détails

Titre: Thermodynamic coupling of the tandem RRM domains of hnRNP A1 underlie its pleiotropic RNA binding functions
Créateurs - sans rôle: Jeffrey D Levengood - Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA
Davit Potoyan - Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Srinivasa Penumutchu - Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA
Abhishek Kumar - Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Qianzi Zhou - Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Yiqing Wang - New York University Grossman School of Medicine, New York, NY 10016, USA
Alexandar L Hansen - CCIC and Gateway NMR Facility, The Ohio State University, Columbus, OH 43210, USA
Sebla Kutluay - Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Julien Roche - Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011, USA
Blanton S Tolbert - Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
Détails de publication: Science advances, Vol.10(28), p.eadk6580
Note de subvention: U54 AI170660 / NIAID NIH HHS R01 AI150830 / NIAID NIH HHS P30 GM124166 / NIGMS NIH HHS R35 GM138243 / NIGMS NIH HHS
Identifiants: 99140159409311
Unité académique: Institut de Recherche en Cancérologie de Montpellier - IRCM
Langue: English
Type de ressource: Journal article