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

doi:10.1016/j.str.2019.02.001

. 2019 May 7;27(5):741-748.e3.

doi: 10.1016/j.str.2019.02.001. Epub 2019 Mar 7.

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

Mutsuko Kukimoto-Niino¹, Kengo Tsuda², Kentaro Ihara², Chiemi Mishima-Tsumagari², Keiko Honda³, Noboru Ohsawa³, Mikako Shirouzu⁴

Affiliations

¹ 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.
² 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.
³ Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan.
⁴ 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.

PMID: 30853411
DOI: 10.1016/j.str.2019.02.001

Free article

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

Mutsuko Kukimoto-Niino et al. Structure. 2019.

Free article

. 2019 May 7;27(5):741-748.e3.

doi: 10.1016/j.str.2019.02.001. Epub 2019 Mar 7.

Authors

Mutsuko Kukimoto-Niino¹, Kengo Tsuda², Kentaro Ihara², Chiemi Mishima-Tsumagari², Keiko Honda³, Noboru Ohsawa³, Mikako Shirouzu⁴

Affiliations

¹ 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.
² 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.
³ Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan.
⁴ 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.

PMID: 30853411
DOI: 10.1016/j.str.2019.02.001

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.

Keywords: Cdc42; DHR-2; DOCK; GEF; GTPase; Rac; Rho; crystal structure; dedicator of cytokinesis; molecular dynamics.

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

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

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