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PLoS Comput Biol. 2018 Nov 9;14(11):e1006364. doi: 10.1371/journal.pcbi.1006364. eCollection 2018 Nov.

Comparative structural dynamic analysis of GTPases.

Author information

1
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, United States of America.
2
Department of Chemistry, Georgia State University, Atlanta, GA, United States of America.
3
Division of Biological Sciences, Section of Molecular Biology, University of California, San Diego, La Jolla, CA, United States of America.

Abstract

GTPases regulate a multitude of essential cellular processes ranging from movement and division to differentiation and neuronal activity. These ubiquitous enzymes operate by hydrolyzing GTP to GDP with associated conformational changes that modulate affinity for family-specific binding partners. There are three major GTPase superfamilies: Ras-like GTPases, heterotrimeric G proteins and protein-synthesizing GTPases. Although they contain similar nucleotide-binding sites, the detailed mechanisms by which these structurally and functionally diverse superfamilies operate remain unclear. Here we compare and contrast the structural dynamic mechanisms of each superfamily using extensive molecular dynamics (MD) simulations and subsequent network analysis approaches. In particular, dissection of the cross-correlations of atomic displacements in both the GTP and GDP-bound states of Ras, transducin and elongation factor EF-Tu reveals analogous dynamic features. This includes similar dynamic communities and subdomain structures (termed lobes). For all three proteins the GTP-bound state has stronger couplings between equivalent lobes. Network analysis further identifies common and family-specific residues mediating the state-specific coupling of distal functional sites. Mutational simulations demonstrate how disrupting these couplings leads to distal dynamic effects at the nucleotide-binding site of each family. Collectively our studies extend current understanding of GTPase allosteric mechanisms and highlight previously unappreciated similarities across functionally diverse families.

Conflict of interest statement

The authors have declared that no competing interests exist.

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