TY - JOUR
T1 - A steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs
AU - Lu, Mingjian
AU - Kinchen, Jason M.
AU - Rossman, Kent L.
AU - Grimsley, Cynthia
AU - Hall, Matthew
AU - Sondek, John
AU - Hengartner, Michael O.
AU - Yajnik, Vijay
AU - Ravichandran, Kodi S.
N1 - Funding Information:
We thank Michiyuki Matsuda for the original Dock180 and the Dock2 plasmids and members of the Ravichandran lab for helpful suggestions during this work. This work was supported by National Institutes of Health grants GM-64709 (to K.S.R.) and DK63933 (to V.Y.), an Infectious Diseases Training grant from the National Institutes of Health (to C.G.), and grants from the Swiss National Science Foundation, The Ernst Hadorn Foundation, and the European Union (FP5 project APOCLEAR) (to M.O.H.).
PY - 2005/2/22
Y1 - 2005/2/22
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/13944277113
U2 - 10.1016/j.cub.2005.01.050
DO - 10.1016/j.cub.2005.01.050
M3 - Article
C2 - 15723800
AN - SCOPUS:13944277113
SN - 0960-9822
VL - 15
SP - 371
EP - 377
JO - Current Biology
JF - Current Biology
IS - 4
ER -