Pathways & interactions
DHR-1 domain (IPR027007)
Short name: DHR-1_domain
Rho guanosine triphosphatases (GTPases) are critical regulators of cell motility, polarity, adhesion, cytoskeletal organisation, 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 with an adjacent 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- homology region (DHR)-1 or CDM-zizimin homology 1 (CZH1) domain and the DHR-2 domain (also termed the CZH2 or DOCKER domain) [PMID: 20713135, PMID: 12172552, PMID: 12432077, PMID: 20167601, PMID: 19745154, PMID: 21613211].
The ~200 residue DHR-1 domain is located toward the N terminus. It adopts a C2-like architecture and interacts with phosphatidylinositol 3,4,5-trisphosphate [PMID: 19745154] to mediate signalling and membrane localization. The central core of the DHR-1 domain adopts an antiparallel beta-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 [PMID: 20167601].
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 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 [PMID: 19745154, PMID: 21613211].
Some DOCK proteins are listed below:
- Mammalian Mammalian dedicator of cytokinesis 180 (DOCK180 or DOCK1), important for cell migration.
- Mammalian DOCK2, important for lymphocyte development, homong, activation, adhesion, polarization and migration processes.
- Mammalian DOCK3 (also known as MOCA), is expressed predominantly in neurons and resides in growth cones and membrane ruffles.
- Mammalian DOCK4, possesses tumor suppressor properties.
- Mammalian DOCK9 (zizimin1), plays an important role in dendrite growth in hippocampal neurons through activation of Cdc42.
- Drosophila melanogaster Myoblast city.
- Caenorhabditis elegans CED-5.