Structural Basis for the Dual Substrate Specificity of DOCK7 Guanine Nucleotide Exchange Factor.

Crystallization Crystallography, X-Ray GTPase-Activating Proteins / chemistry Guanine Nucleotide Exchange Factors / chemistry Humans Molecular Conformation Molecular Dynamics Simulation Mutagenesis Substrate Specificity cdc42 GTP-Binding Protein / chemistry rac1 GTP-Binding Protein / chemistry
Cdc42 DHR-2 DOCK GEF GTPase Rac Rho crystal structure dedicator of cytokinesis molecular dynamics

Journal

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

Informations de publication

Date de publication:
07 05 2019
Historique:
received: 04 09 2018
revised: 18 12 2018
accepted: 04 02 2019
pubmed: 12 3 2019
medline: 9 6 2020
entrez: 12 3 2019
Statut: ppublish

Résumé

The Dedicator Of CytoKinesis (DOCK) family of atypical guanine nucleotide exchange factors activates the Rho family GTPases Rac and/or Cdc42 through DOCK homology region 2 (DHR-2). Previous structural analyses of the DHR-2 domains of DOCK2 and DOCK9 have shown that they preferentially bind Rac1 and Cdc42, respectively; however, the molecular mechanism by which DHR-2 distinguishes between these GTPases is unclear. Here we report the crystal structure of the Cdc42-bound form of the DOCK7 DHR-2 domain showing dual specificity for Rac1 and Cdc42. The structure revealed increased substrate tolerance of DOCK7 at the interfaces with switch 1 and residue 56 of Cdc42. Furthermore, molecular dynamics simulations showed a closed-to-open conformational change in the DOCK7 DHR-2 domain between the Cdc42- and Rac1-bound states by lobe B displacement. Our results suggest that lobe B acts as a sensor for identifying different switch 1 conformations and explain how DOCK7 recognizes both Rac1 and Cdc42.

Identifiants

DOI: 10.1016/j.str.2019.02.001 PMID: 30853411
pubmed: 30853411
pii: S0969-2126(19)30045-0
doi: 10.1016/j.str.2019.02.001
pii:
doi:

Substances chimiques

DOCK7 protein, human 0
GTPase-Activating Proteins 0
Guanine Nucleotide Exchange Factors 0
RAC1 protein, human 0
CDC42 protein, human EC 3.6.5.2
cdc42 GTP-Binding Protein EC 3.6.5.2
rac1 GTP-Binding Protein EC 3.6.5.2

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

741-748.e3

Informations de copyright

Copyright © 2019 Elsevier Ltd. All rights reserved.

Auteurs

Mutsuko Kukimoto-Niino (M)

Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa 230-0045, Japan; Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan. Electronic address: kukimoto@riken.jp.

Kengo Tsuda (K)

Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa 230-0045, Japan; Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan.

Kentaro Ihara (K)

Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa 230-0045, Japan; Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan.

Chiemi Mishima-Tsumagari (C)

Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa 230-0045, Japan; Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan.

Keiko Honda (K)

Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan.

Noboru Ohsawa (N)

Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan.

Mikako Shirouzu (M)

Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa 230-0045, Japan; Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan. Electronic address: mikako.shirouzu@riken.jp.

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Classifications MeSH

questionsmedicales.fr › Phénomènes chimiques › Cristallisation › Structural Basis for the Dual Substrate...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Cristallographie aux rayons X › Structural Basis for the Dual Substrate...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Régulateurs des protéines G › Protéines d'activation de la GTPase › Structural Basis for the Dual Substrate...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Régulateurs des protéines G › Facteurs d'échange de nucléotides guanyliques › Structural Basis for the Dual Substrate...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Structural Basis for the Dual Substrate...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Structural Basis for the Dual Substrate...
questionsmedicales.fr › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de dynamique moléculaire › Structural Basis for the Dual Substrate...
questionsmedicales.fr › Phénomènes génétiques › Mutagenèse › Structural Basis for the Dual Substrate...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Spécificité du substrat › Structural Basis for the Dual Substrate...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines G › Protéines G monomériques › Protéines G rho › Protéine G cdc42 › Structural Basis for the Dual Substrate...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines G › Protéines G monomériques › Protéines G rho › Protéines G rac › Protéine G rac1 › Structural Basis for the Dual Substrate...