|PROSITE documentation PDOC51650 [for PROSITE entry PS51651]|
Rho guanosine triphosphatases (GTPases) are critical regulators of cell motility, polarity, adhesion, cytoskeletal organization, proliferation, gene expression, 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 (see <PDOC00605>) with an adjacent pleckstrin homology (PH) domain (see <PDOC50003>) 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-homology region (DHR)-1 or CDM-zizimin homology 1 (CZH1) domain and the DHR-2 domain (also termed the CZH2 or DOCKER domain) [1,2,3,4,5].
The ~200 residue DHR-1 domain is located toward the N-terminus. It adopts a C2-like architecture (see <PDB:3L4C>) and interacts with phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] to mediate signalling and membrane localization. The central core of the DHR-1 domain adopts an antiparallel β-sandwich with the "type II" C2 domain fold (a circular permutation of the more common "type I" topology), in which two 4-stranded sheets with strand order 6-5-2-3 and 7-8-1-4 create convex- and concave-exposed faces, respectively .
The DHR-2 domain is a GEF catalytic domain of ~400 residues situated within the C-terminus. The structure of the DHR2 domain differs from that of other GEF catalytic domains. It is organized into three lobes of roughly equal size (lobes A, B, and C), with the Rho-family binding site and catalytic center generated entirely from lobes B and C (see <PDB:2WM9>). Lobe A is formed from an antiparallel array of α helices. Through extensive contacts with lobe B, lobe A stabilizes the DHR2 domain. Lobe B adopts an unusal architecture of two antiparallel β sheets disposed in a loosely packed orthogonal arrangement, whereas lobe C comprises a four-helix bundle [4,5] .
Some DOCK proteins are listed below:
The profiles we developed cover the entire DHR-1 and DHR-2 domains.Last update:
July 2012 / First entry.
PROSITE methods (with tools and information) covered by this documentation:
|1||Authors||Meller N. Irani-Tehrani M. Kiosses W.B. Del Pozo M.A. Schwartz M.A.|
|Title||Zizimin1, a novel Cdc42 activator, reveals a new GEF domain for Rho proteins.|
|Source||Nat. Cell Biol. 4:639-647(2002).|
|2||Authors||Cote J.-F. Vuori K.|
|Title||Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity.|
|Source||J. Cell Sci. 115:4901-4913(2002).|
|3||Authors||Premkumar L. Bobkov A.A. Patel M. Jaroszewski L. Bankston L.A. Stec B. Vuori K. Cote J.-F. Liddington R.C.|
|Title||Structural basis of membrane targeting by the Dock180 family of Rho family guanine exchange factors (Rho-GEFs).|
|Source||J. Biol. Chem. 285:13211-13222(2010).|
|4||Authors||Yang J. Zhang Z. Roe S.M. Marshall C.J. Barford D.|
|Title||Activation of Rho GTPases by DOCK exchange factors is mediated by a nucleotide sensor.|
|5||Authors||Kulkarni K. Yang J. Zhang Z. Barford D.|
|Title||Multiple factors confer specific Cdc42 and Rac protein activation by dedicator of cytokinesis (DOCK) nucleotide exchange factors.|
|Source||J. Biol. Chem. 286:25341-25351(2011).|