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

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作者：

M Lu，JM Kinchen，KL Rossman，C Grimsley，M Hall，J Sondek，MO Hengartner，V Yajnik，KS Ravichandran

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摘要：

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.

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关键词：

CELL-MIGRATION CRKII/DOCK180/RAC PATHWAY RAC ACTIVATION MYOBLAST CITY PROTEIN PHAGOCYTOSIS MEMBRANE COMPLEX DOMAIN MEMBER