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

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

Authors :
Kukimoto-Niino, Mutsuko
Tsuda, Kengo
Ihara, Kentaro
Mishima-Tsumagari, Chiemi
Honda, Keiko
Ohsawa, Noboru
Shirouzu, Mikako
Source :
Structure. May2019, Vol. 27 Issue 5, p741-741. 1p.
Publication Year :
2019

Abstract

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. • Crystal structure of DOCK7 DHR-2 has been solved in complex with Cdc42 • Structural compatibility accounts for the dual specificity of DOCK7 for Rac and Cdc42 • MD simulations suggest a conformational change of DOCK7 DHR-2 in complex with Rac1 • Structure-based mutagenesis identified specificity determinants of DOCK7 DOCK7 enhances guanine nucleotide exchange of both Rac1 and Cdc42. Kukimoto-Niino et al. report the crystal structure of the DOCK7 DHR-2 domain complexed with Cdc42. They show that the compatibility of the interface and the predicted conformational change of the domain are important for the dual substrate specificity of DOCK7. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
09692126
Volume :
27
Issue :
5
Database :
Academic Search Index
Journal :
Structure
Publication Type :
Academic Journal
Accession number :
136155291
Full Text :
https://doi.org/10.1016/j.str.2019.02.001