|PROSITE documentation PDOC00605 [for PROSITE entry PS50010]|
The Rho family GTPases Rho, Rac and CDC42 regulate a diverse array of cellular processes. Like all members of the Ras superfamily, the Rho proteins cycle between active GTP-bound and inactive GDP-bound conformational states. Activation of Rho proteins, through release of bound GDP and subsequent binding of GTP, is catalyzed by guanine nucleotide exchange factors (GEFs) in the Dbl family. The proteins encoded by members of the Dbl family share a common domain of about 200 residues (designated the Dbl homology or DH domain) that has been shown to encode a GEF activity specific for a number of Rho family members. In addition, all family members possess a second, shared domain designated the pleckstrin homology (PH) domain (see <PDOC50003>). Trio and its homolog UNC-73 are unique within the Dbl family insomuch as they encode two distinct DH/PH domain modules. The PH domain is invariably located immediately C-terminal to the DH domain and this invariant topography suggests a functional interdependence between these two structural modules. Biochemical data have established the role of the conserved DH domain in Rho GTPase interaction and activation, and the role of the tandem PH domain in intracellular targeting and/or regulation of DH domain function. The DH domain of Dbl has been shown to mediate oligomerization that is mostly homophilic in nature. In addition to the tandem DH/PH domains Dbl family GEFs contain diverse structural motifs like serine/threonine kinase (see <PDOC00100>), RBD, PDZ (see <PDOC50106>), RGS (see <PDOC50132>), IQ (see <PDOC50096>), REM, Cdc25 RasGEF (see <PDOC00594>), CH (see <PDOC50021>), SH2 (see <PDOC50001>), SH3 (see <PDOC50002>), EF (see <PDOC00018>), spectrin or Ig [1,2,3,4].
The DH domain is composed of three structurally conserved regions separated by more variable regions. It does not share significant sequence homology with other subtypes of small G-protein GEF motifs such as the Cdc25 domain and the Sec7 domain (see <PDOC50190>), which specifically interact with Ras and ARF family small GTPases, respectively, nor with other Rho protein interactive motifs, indicating that the Dbl family proteins are evolutionarily unique. The DH domain is composed of 11 α helices that are folded into a flattened, elongated α-helix bundle in which two of the three conserved regions, conserved region 1 (CR1) and conserved region 3 (CR3), are exposed near the center of one surface. CR1 and CR3, together with a part of α-6 and the DH/PH junction site, constitute the Rho GTPase interacting pocket [2,3,5].
Some proteins known to contain a DH domain are listed below:
The profile we developed covers the entire DH domain.Last update:
April 2006 / Pattern revised.
PROSITE methods (with tools and information) covered by this documentation:
|1||Authors||Hart M.J., Eva A., Zangrilli D., Aaronson S.A., Evans T., Cerione R.A., Zheng Y.|
|Title||Cellular transformation and guanine nucleotide exchange activity are catalyzed by a common domain on the dbl oncogene product.|
|Source||J. Biol. Chem. 269:62-65(1994).|
|2||Authors||Whitehead I.P., Campbell S., Rossman K.L., Der C.J.|
|Title||Dbl family proteins.|
|Source||Biochim. Biophys. Acta 1332:F1-23(1997).|
|Title||Dbl family guanine nucleotide exchange factors.|
|Source||Trends Biochem. Sci. 26:724-732(2001).|
|4||Authors||Zhu K., Debreceni B., Bi F., Zheng Y.|
|Title||Oligomerization of DH domain is essential for Dbl-induced transformation.|
|Source||Mol. Cell. Biol. 21:425-437(2001).|
|5||Authors||Aghazadeh B., Zhu K., Kubiseski T.J., Liu G.A., Pawson T., Zheng Y., Rosen M.K.|
|Title||Structure and mutagenesis of the Dbl homology domain.|
|Source||Nat. Struct. Biol. 5:1098-1107(1998).|