Crystal structure of the Rac activator, asef, reveals its autoinhibitory mechanism

Kazutaka Murayama, Mikako Shirouzu, Yoshihiro Kawasaki, Miyuki Kato-Murayama, Kyoko Hanawa-Suetsugu, Ayako Sakamoto, Yasuhiro Katsura, Atsushi Suenaga, Mitsutoshi Toyama, Takaho Terada, Makoto Taiji, Tetsu Akiyama, Shigeyuki Yokoyama

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43 Citations (Scopus)

Abstract

The Rac-specific guanine nucleotide exchange factor (GEF) Asef is activated by binding to the tumor suppressor adenomatous polyposis coli mutant, which is found in sporadic and familial colorectal tumors. This activated Asef is involved in the migration of colorectal tumor cells. The GEFs for Rho family GTPases contain the Dbl homology (DH) domain and the pleckstrin homology (PH) domain. When Asef is in the resting state, the GEF activity of the DH-PH module is intramolecularly inhibited by an unidentified mechanism. Asef has a Src homology 3 (SH3) domain in addition to the DH-PH module. In the present study, the three-dimensional structure of Asef was solved in its autoinhibited state. The crystal structure revealed that the SH3 domain binds intramolecularly to the DH domain, thus blocking the Rac-binding site. Furthermore, the RT-loop and the C-terminal region of the SH3 domain interact with the DH domain in a manner completely different from those for the canonical binding to a polyproline-peptide motif. These results demonstrate that the blocking of the Rac-binding site by the SH3 domain is essential for Asef autoinhibition. This may be a common mechanism in other proteins that possess an SH3 domain adjacent to a DH-PH module.

Original languageEnglish
Pages (from-to)4238-4242
Number of pages5
JournalJournal of Biological Chemistry
Volume282
Issue number7
DOIs
Publication statusPublished - 2007 Feb 16

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Murayama, K., Shirouzu, M., Kawasaki, Y., Kato-Murayama, M., Hanawa-Suetsugu, K., Sakamoto, A., Katsura, Y., Suenaga, A., Toyama, M., Terada, T., Taiji, M., Akiyama, T., & Yokoyama, S. (2007). Crystal structure of the Rac activator, asef, reveals its autoinhibitory mechanism. Journal of Biological Chemistry, 282(7), 4238-4242. https://doi.org/10.1074/jbc.C600234200