DBL homology domain from beta-PIX
Homo sapiens (human)
GTPases (GTP binding proteins) are a family of proteins that bind to GTP in their active form. They catalyze the hydrolysis of GTP to GDP through the loss of a phosphate and undergo a conformational change to become inactive. When active, these proteins stimulate signaling pathways through a cascade of protein phosphorylations. The activation of GTPases is regulated by GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). GAPs bind to GTPases and induce them to hydrolyze the GTP to GDP thus inactivating the protein. The GDP stays tightly bound to the GTPase till it encounters a GEF. GEFs are proteins that activate GTPases by facilitating the release of bound GDP and allowing the binding of GTP. Thus GAPs inactivate the GTPase and GEFs activate it. The Dbl family of GEFs functions by activating the Rho proteins, which are involved in the formation of actin stress fibers and focal adhesions along with regulating gene expression and cell cycle progression. All the members of the Dbl family of proteins have a ~200 residue Dbl homology (DH) domain. The DH domain is considered to be the region of GEF activity. Most of them also have a ~100 residue pleckstrin homology (PH) domain next to the DH domain. The PH domain is a signaling domain involved in intracellular membrane targeting.
The structure shown above is that of the DH domain of human PAK-interacting exchange protein (beta-PIX). The DH domain consists of 11 alpha helices forming a flattened, elongated bundle. The GTPase interaction site is on one of the faces of the enlongated bundle and is formed by three conserved helices. This active surface is largely hydrophilic with an adjacent depression of hydrophobic residues. Since the GTPase binding site is at the DH-domain C terminus, and thus very close to the PH domain, it is possible that the two domains may communicate to regulate the GTPase interactions and GEF activity in vivo.
Protein Data Bank (PDB)
Aghazadeh, B. Zhu, K. Kubiseski, T.J. Liu, G.A. Pawson, T. Zheng, Y. Rosen, M.K.; "Structure and Mutagenesis of the Dbl Homology Domain"; Nature Struct. Biol.; (1998) 5:1098-1107 PubMed:9846881.
author: Ashwini Patil