PROSITE documentation PDOC50200

Ras-associating (RA) domain profile

Ras proteins are signal-transducing GTPases that cycle between inactive GDP-bound and active GTP-bound forms. Ras is a prolific signalling molecule interacting with a spectrum of effector molecules and acting through more than one signalling pathway. A domain of about 100 residues, termed RA for RalGDS/AF-6 or Ras-Associating, interacts with Ras and other small GTPases. It occurs in one or two copies in a variety of signalling molecules. It can be found associated with many other domains, such as PDZ (see <PDOC50106>), Dilute (DIL), GEF (see <PDOC00594>), myosin motor, IQ (see <PDOC50096>), C1 (see <PDOC00379>), C2 (see <PDOC00380>), protein kinase (see <PDOC00100>), VPS9 or sterile α motif (SAM) (see <PDOC50105>) [1,2,3].

Some proteins known to contain a RA domain are listed below:

• Mammalian Ral guanine nucleotide dissociation stimulator (RalGDS).
• Human AF-6 protein and Drosophila CNO protein, two orthologous modular proteins containing myosin- and kinesin-like cargo-binding domains.
• Mammalian Ral guanine nucleotide dissociation stimulator-like 1 and 2 (RGL1 and RGL2).
• Mammalian Ras and Rab interactor 1 (RIN1), 2 (RIN2) and 3 (RIN3).
• Mammalian adapter proteins of the Grb7/10/14 family. They bind, through their C-terminal SH2 domain (see <PDOC50001>), phosphotyrosine-containing sequences on a variety of activated tyrosine kinase receptors.
• Caenorhabditis elegans protein mig-10.
• Animal phosphoinositide-specific phospholipase C PLC-epsilon.
• Animal unconventional myosins IX.
• Mammalian diacylglycerol kinases, theta (EC 2.7.1.107).
• Fungal-type adenylate cyclase (EC 4.6.1.1).
• Yeast STE50 protein. It is involved in growth arrest during conjugation and may interact with the G protein α subunit.
• Fission yeast sexual differentiation protein ste4. It is essential for mating and meiosis.
• Smut fungus MAP kinase pathway-interacting protein Ubc2.

Structurally, the RA domain of RalGDS consists of a five-stranded mixed β-sheet interrupted by a 12 residue α-helix and two additional small α-helices (see <PDB:1LXD>). The structure of the RA domain belongs to the ubiquitin α/β roll superfold and is similar to that of the RBD domain and the N-terminal third of the FERM domain (see <PDOC00566>) [4,5]. The RA domain forms a homodimer where the interdimer surface is composed of two cysteines (Cys 2 in each monomer) forming an intermolecular disulfide bond and two interacting intermolecular antiparallel β-sheets [4]. The major interaction between Ras and RalGDS RA domain occurs between two antiparallel β-strands: β 2 of Ras and β 2 of RA. This interaction occurs both at the backbone as well as the side chain level (see <PDB:1LFD>) [6].

The profile we developed covers the entire RA domain.