This entry represents the Spa2 homology domain (SHD) domain found in the yeast Spa2/Sph1 protein and the mammalian GIT proteins. Budding yeast Spa2 is a component of the polarisome that functions in actin cytoskeletal organisation during polarized growth []. Its paralogue, Sph1, is involved in shmoo formation and bipolar bud site selection []. GIT is a GTPase-activating protein for the ADP ribosylation factor family. It may serve as a scaffold to bring together molecules to form signaling modules controlling vesicle trafficking, adhesion and cytoskeletal organisation []. Mutations in the Spa2 homology domain (SHD) domain of GIT1 described here interfere with the association of GIT1 with Piccolo, beta-PIX, and focal adhesion kinase [].
This entry represents the C-terminal domain of the ARF GTPase-activating protein GIT1. GIT1 is an ArfGAP and scaffolding protein regulating cell adhesion and migration []. To perform this function, it localises p21-activated kinase (PAK) and PAK-interactive exchange factor to focal adhesions. Its activation is regulated by interaction between its paxillin-binding C-terminal and the LD motifs of paxillin. The C-terminal folds into a four helix bundle.
There are two forms of Pix proteins: alpha Pix (also called Rho guanine nucleotide exchange factor (GEF) 6, 90Cool-2 or ARHGEF6) and beta Pix (GEF7, p85Cool-1 or ARHGEF7), which activate small GTPases by exchanging bound GDP for free GTP. betaPix contains an N-terminal SH3 domain, a RhoGEF/DH domain, a PH domain, a GIT1 binding domain (GBD), and a C-terminal coiled-coil (CC) domain []. It acts as a GEF for both Cdc42 and Rac1 [], and plays important roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion [, , , ]. alphaPix differs in that it contains a calponin homology (CH) domain, which interacts with beta-parvin, N-terminal to the SH3 domain. alphaPix is an exchange factor for Rac1 and Cdc42 and mediates Pak activation on cell adhesion to fibronectin. Mutations in alphaPix can cause X-linked mental retardation. alphaPix also interacts with Huntington's disease protein (htt), and enhances the aggregation of mutant htt (muthtt) by facilitating SDS-soluble muthtt-muthtt interactions. The DH-PH domain of a Pix was required for its binding to htt. In the majority of Rho GEF proteins, the DH-PH domain is responsible for the exchange activity [, , , , ].This entry represents the PH domain of ARHGEF6 and ARHGEF7.
