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PROSITE documentation PDOC51650 [for PROSITE entry PS51651]

DHR-1 and DHR-2 domain profiles





Description

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 [3].

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:

  • 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.

The profiles we developed cover the entire DHR-1 and DHR-2 domains.

Last update:

July 2012 / First entry.

Technical section

PROSITE methods (with tools and information) covered by this documentation:

DHR_2, PS51651; DHR-2 domain profile  (MATRIX)

DHR_1, PS51650; DHR-1 domain profile  (MATRIX)


References

1AuthorsMeller N. Irani-Tehrani M. Kiosses W.B. Del Pozo M.A. Schwartz M.A.
TitleZizimin1, a novel Cdc42 activator, reveals a new GEF domain for Rho proteins.
SourceNat. Cell Biol. 4:639-647(2002).
PubMed ID12172552
DOI10.1038/ncb835

2AuthorsCote J.-F. Vuori K.
TitleIdentification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity.
SourceJ. Cell Sci. 115:4901-4913(2002).
PubMed ID12432077

3AuthorsPremkumar L. Bobkov A.A. Patel M. Jaroszewski L. Bankston L.A. Stec B. Vuori K. Cote J.-F. Liddington R.C.
TitleStructural basis of membrane targeting by the Dock180 family of Rho family guanine exchange factors (Rho-GEFs).
SourceJ. Biol. Chem. 285:13211-13222(2010).
PubMed ID20167601
DOI10.1074/jbc.M110.102517

4AuthorsYang J. Zhang Z. Roe S.M. Marshall C.J. Barford D.
TitleActivation of Rho GTPases by DOCK exchange factors is mediated by a nucleotide sensor.
SourceScience 325:1398-1402(2009).
PubMed ID19745154
DOI10.1126/science.1174468

5AuthorsKulkarni K. Yang J. Zhang Z. Barford D.
TitleMultiple factors confer specific Cdc42 and Rac protein activation by dedicator of cytokinesis (DOCK) nucleotide exchange factors.
SourceJ. Biol. Chem. 286:25341-25351(2011).
PubMed ID21613211
DOI10.1074/jbc.M111.236455



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