A steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs

Mingjian Lu, Jason M. Kinchen, Kent L. Rossman, Cynthia Grimsley, Matthew Hall, John Sondek, Michael O. Hengartner, Vijay Yajnik, Kodi S. Ravichandran

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

CDM (CED-5, Dock180, Myoblast city) family members have been recently identified as novel, evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases [1-7]. They regulate multiple processes, including embryonic development, cell migration, apoptotic-cell engulfment, tumor invasion, and HIV-1 infection, in diverse model systems [4, 6, 8-16]. However, the mechanism(s) of regulation of CDM proteins has not been well understood. Here, our studies on the prototype member Dock180 reveal a steric-inhibition model for regulating the Dock180 family of GEFs. At basal state, the N-terminal SH3 domain of Dock180 binds to the distant catalytic Docker domain and negatively regulates the function of Dock180. Further studies revealed that the SH3:Docker interaction sterically blocks Rac access to the Docker domain. Interestingly, ELMO binding to the SH3 domain of Dock180 disrupted the SH3:Docker interaction, facilitated Rac access to the Docker domain, and contributed to the GEF activity of the Dock180/ELMO complex. Additional genetic rescue studies in C. elegans suggested that the regulation of the Docker-domain-mediated GEF activity by the SH3 domain and its adjoining region is evolutionarily conserved. This steric-inhibition model may be a general mechanism for regulating multiple SH3-domain-containing Dock180 family members and may have implications for a variety of biological processes.

Original languageEnglish
Pages (from-to)371-377
Number of pages7
JournalCurrent Biology
Volume15
Issue number4
DOIs
StatePublished - Feb 22 2005

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