4kvg

Crystal structure of RIAM RA-PH domains in complex with GTP bound Rap1

spinqualitylabelsall models 4kvg, resolution 1.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4kvg is a 4 chain structure with sequence from Human and Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO, GTP, MG Gene: KREV1, RAP1A (HUMAN), Apbb1ip, Prel1 (LK3 transgenic mice) Resources: FirstGlance, OCA, RCSB, PDBsum Function [RAP1A_HUMAN] Induces morphological reversion of a cell line transformed by a Ras oncogene. Counteracts the mitogenic function of Ras, at least partly because it can interact with Ras GAPs and RAF in a competitive manner. [AB1IP_MOUSE] Appears to function in the signal transduction from Ras activation to actin cytoskeletal remodeling. Suppresses insulin-induced promoter activities through AP1 and SRE. Mediates Rap1-induced adhesion (By similarity). Publication Abstract from PubMed The small GTPase Rap1 induces integrin activation via an inside-out signaling pathway mediated by the Rap1-interacting adaptor molecule (RIAM). Blocking this pathway may suppress tumor metastasis and other diseases that are related to hyperactive integrins. However, the molecular basis for the specific recognition of RIAM by Rap1 remains largely unknown. Herein we present the crystal structure of an active, GTP-bound GTPase domain of Rap1 in complex with the Ras association (RA)-pleckstrin homology (PH) structural module of RIAM at 1.65 A. The structure reveals that the recognition of RIAM by Rap1 is governed by side-chain interactions. Several side chains are critical in determining specificity of this recognition, particularly the Lys31 residue in Rap1 that is oppositely charged compared with the Glu31/Asp31 residue in other Ras GTPases. Lys31 forms a salt bridge with RIAM residue Glu212, making it the key specificity determinant of the interaction. We also show that disruption of these interactions results in reduction of Rap1:RIAM association, leading to a loss of co-clustering and cell adhesion. Our findings elucidate the molecular mechanism by which RIAM mediates Rap1-induced integrin activation. The crystal structure also offers new insight into the structural basis for the specific recruitment of RA-PH module-containing effector proteins by their small GTPase partners. The structure of Rap1 in complex with RIAM reveals specificity determinants and recruitment mechanism.,Zhang H, Chang YC, Brennan ML, Wu J J Mol Cell Biol. 2014 Apr;6(2):128-39. doi: 10.1093/jmcb/mjt044. Epub 2013 Nov, 28. PMID:24287201 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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