Logo image
Back
Role of Nucleotide Binding and GTPase Domain Dimerization in Dynamin-like Myxovirus Resistance Protein A for GTPase Activation and Antiviral Activity
Journal article   Open access   Peer reviewed

Role of Nucleotide Binding and GTPase Domain Dimerization in Dynamin-like Myxovirus Resistance Protein A for GTPase Activation and Antiviral Activity

Alexej Dick, Laura Graf, Daniel Olal, Alexander von der Malsburg, Song Gao, Georg Kochs and Oliver Daumke
The Journal of biological chemistry, v 290(20), pp 12779-12792
15 May 2015
DOI: https://doi.org/10.1074/jbc.M115.650325
PMID: 25829498
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1074/jbc.M115.650325View
Published, Version of Record (VoR) Open

Abstract

antiviral response catalytic mechanism dynamin-like protein G protein innate immunity interferon membrane Mx proteins viral replication
Myxovirus resistance (Mx) GTPases are induced by interferon and inhibit multiple viruses, including influenza and human immunodeficiency viruses. They have the characteristic domain architecture of dynamin-related proteins with an N-terminal GTPase (G) domain, a bundle signaling element, and a C-terminal stalk responsible for self-assembly and effector functions. Human MxA (also called MX1) is expressed in the cytoplasm and is partly associated with membranes of the smooth endoplasmic reticulum. It shows a protein concentration-dependent increase in GTPase activity, indicating regulation of GTP hydrolysis via G domain dimerization. Here, we characterized a panel of G domain mutants in MxA to clarify the role of GTP binding and the importance of the G domain interface for the catalytic and antiviral function of MxA. Residues in the catalytic center of MxA and the nucleotide itself were essential for G domain dimerization and catalytic activation. In pulldown experiments, MxA recognized Thogoto virus nucleocapsid proteins independently of nucleotide binding. However, both nucleotide binding and hydrolysis were required for the antiviral activity against Thogoto, influenza, and La Crosse viruses. We further demonstrate that GTP binding facilitates formation of stable MxA assemblies associated with endoplasmic reticulum membranes, whereas nucleotide hydrolysis promotes dynamic redistribution of MxA from cellular membranes to viral targets. Our study highlights the role of nucleotide binding and hydrolysis for the intracellular dynamics of MxA during its antiviral action. Human myxovirus resistance protein A (MxA) is an antiviral dynamin-related GTPase. Dimerization of MxA via a GTPase domain interface is required for GTP hydrolysis and antiviral activity. GTP binding allows GTPase domain dimerization and membrane-associated assembly of MxA, but it is not sufficient to induce a sustained antiviral effect. New mechanistic insights into the antiviral action of MxA are provided.

Metrics

9 Record Views
48 citations in Web of Science
47 citations in Scopus

Details

UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

InCites Highlights

Data related to this publication, from InCites Benchmarking & Analytics tool:

Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Biochemistry & Molecular Biology
Logo image