Ras-associating (RA) domain found in Ral guanine nucleotide dissociation stimulator (RalGDS) and similar proteins
RalGDS, also termed Ral guanine nucleotide exchange factor (RalGEF), is a guanine exchange factor (GEF) for the Ral family of small GTPases. It is the prototype of RalGDS family proteins that are involved in Ras and Ral signaling pathways as downstream effector proteins. RalGDS stimulates the dissociation of GDP from the Ras-related RalA and RalB GTPases which allows GTP binding and activation of the GTPases. It interacts and acts as an effector molecule for R-Ras, H-Ras, K-Ras, and Rap. Moreover, RalGDS functions as a novel interacting partner for Rab7-interacting lysosomal protein (RILP), a key regulator for late endosomal/lysosomal trafficking. RILP suppresses invasion of breast cancer cells by inhibiting the GEF activity for RalA of RalGDS. RalGDS also plays a vital role in the regulation of Ral-dependent Weibel-Palade bodies (WPB) exocytosis from endothelial cells. In addition, RalGDS couples growth factor signaling to Akt activation by promoting PDK1-induced Akt phosphorylation. Members in this family have similar domain structure: a central CDC25 homology domain with an upstream Ras Exchange motif (REM), and a C-terminal Ras-associating (RA) domain. The RA domain has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin; ubiquitin is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair.
Feature 1:RA-Ras interaction site [polypeptide binding site]
Evidence:
Comment:All RA domains have the common ubiquitin fold but not all of them bind to Ras proteins
Comment:Computational and manual sequence and structure analysis of RA domains show the positively charged sequence epitopes of its ubiquitin fold (beta1, beta2 and alpha1) which are located at similar positions are the hot spots of the binding interface to Ras.
Comment:The Ras protein signals to a number of distinct pathways by interacting with diverse downstream effectors. In the case of the Ras-RA_RalGDs complex a second RA_RalGDS molecule also interacts with a different part of the Ras molecule.
Structure:1LFD; Rattus norvegicus RA domain of RalGDS in complex with Ras, contacts at 4A.
Jiyao W et al.(2023). "The conserved domain database in 2023.",