PROSITE documentation PDOC00605

Dbl homology (DH) domain signature and profile

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:

• Dbl (or mcf-2) oncogene from mammals. Dbl is a GEF for a ras-like protein known as G25K or CDC42Hs.
• CDC24 from yeast. CDC24 is a GEF that acts on the ras-like protein CDC42 to regulate bud site assembly and mating pheromone signaling.
• scd1 from fission yeast. It is a cell cycle regulatory protein with global homology to CDC24.
• p140-RAS GEF (cdc25Mm) from mammals. This protein, a GEF for ras, possesses both a domain belonging to the CDC24 family and one belonging to the CDC25 family.
• Break cluster region (Bcr) oncogene from mammals. Bcr can form a chimera with the abl protein and then cause chronic myelogenous leukemia (CML). Bcr acts on p21-rac proteins.
• Abr, a protein that shares strong sequence organization and identity with Bcr, but lacks the serine/threonine kinase domain that is found at the N- terminus of Bcr.
• T-lymphoma invasion and metastasis inducing protein 1 (Tiam1 protein). Acts as a GEF for rac1, CDC42, and to a lesser extent rhoA.
• Oncogenes vav and vav2 from mammals. The target of these proteins are not yet known.
• Oncogene ect2 from mouse. The target of this protein is not yet known.

The profile we developed covers the entire DH domain.