InterPro domain: IPR027357

Rho guanosine triphosphatases (GTPases) are critical regulators of cell motility, polarity, adhesion, cytoskeletal organisation, proliferation, geneexpression, and apoptosis. Conversion of these biomolecular switches to the activated GTP-bound state is controlled by two families of guanine nucleotide exchanges factors (GEFs). DH-PH proteins are a large group of Rho GEFs comprising a catalytic Dbl homology (DH) domain with anadjacent pleckstrin homology (PH) domain within the context of functionally diverse signalling modules. The evolutionarily distinct and smaller family of DOCK (dedicator of cytokinesis) or CDM (CED-5, DOCK1180, Myoblast city) proteins activate either Rac or Cdc42 to control cell migration, morphogenesis, and phagocytosis. DOCK proteins share the DOCK-type C2 domain (also termed the DOCK-homology region (DHR)-1 or CDM-zizimin homology 1 (CZH1) domain and the DOCKER domain (also termed the DHR-2 or CZH2 domain) [ 1 , 2 , 3 , 4 , 5 , 6 ].

The DOCK-type C2 domain is located toward the N terminus [ 7 ]. The DOCKER domain is a GEF catalytic domain of ~400 residues situated within the C terminus. The structure of the DOCKER domain differs from that of other GEF catalytic domains. It is organised into three lobes of roughly equal size (lobes A, B, and C), with the Rho-family binding site and catalytic centre generated entirely from lobes B and C. Lobe A is formed from an antiparallel array of alpha helices. Through extensive contacts with lobe B, lobe A stabilises the DHR2 domain. Lobe B adopts an unusual architecture of two antiparallel beta sheets disposed in a loosely packed orthogonal arrangement, whereas lobe C comprises a four-helix bundle [ 7 , 7 ].

This entry represents the DOCKER domain.

1. Zizimin1, a novel Cdc42 activator, reveals a new GEF domain for Rho proteins. Nat. Cell Biol. 4, 639-47
2. Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity. J. Cell. Sci. 115, 4901-13
3. Structural basis of membrane targeting by the Dock180 family of Rho family guanine exchange factors (Rho-GEFs). J. Biol. Chem. 285, 13211-22
4. Activation of Rho GTPases by DOCK exchange factors is mediated by a nucleotide sensor. Science 325, 1398-402
5. Multiple factors confer specific Cdc42 and Rac protein activation by dedicator of cytokinesis (DOCK) nucleotide exchange factors. J. Biol. Chem. 286, 25341-51
6. Structural Basis for the Dual Substrate Specificity of DOCK7 Guanine Nucleotide Exchange Factor. Structure 27, 741-748.e3