| Structural highlights
Function
[GRP2_MOUSE] Functions as a calcium- and DAG-regulated nucleotide exchange factor specifically activating Rap through the exchange of bound GDP for GTP. May also activates other GTPases such as RRAS, RRAS2, NRAS, KRAS but not HRAS. Functions in aggregation of platelets and adhesion of T-lymphocytes and neutrophils probably through inside-out integrin activation. May function in the muscarinic acetylcholine receptor M1/CHRM1 signaling pathway.[1] [2] [3] [4] [5] [6] [7] [8] [9] [LCP2_HUMAN] Involved in T-cell antigen receptor mediated signaling.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The SH3 domain, which normally recognizes proline-rich sequences, has the potential to bind motifs with an RxxK consensus. To explore this novel specificity, we have determined the solution structure of the Gads T cell adaptor C-terminal SH3 domain in complex with an RSTK-containing peptide, representing its physiological binding site on the SLP-76 docking protein. The SLP-76 peptide engages four distinct binding pockets on the surface of the Gads SH3 domain and upon binding adopts a unique structure characterized by a right-handed 3(10) helix at the RSTK locus, in contrast to the left-handed polyproline type II helix formed by canonical proline-rich SH3 ligands. The structure, and supporting mutagenesis and peptide binding data, reveal a novel mode of ligand recognition by SH3 domains.
Structural basis for specific binding of the Gads SH3 domain to an RxxK motif-containing SLP-76 peptide: a novel mode of peptide recognition.,Liu Q, Berry D, Nash P, Pawson T, McGlade CJ, Li SS Mol Cell. 2003 Feb;11(2):471-81. PMID:12620234[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kawasaki H, Springett GM, Toki S, Canales JJ, Harlan P, Blumenstiel JP, Chen EJ, Bany IA, Mochizuki N, Ashbacher A, Matsuda M, Housman DE, Graybiel AM. A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia. Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13278-83. PMID:9789079
- ↑ Ohba Y, Mochizuki N, Yamashita S, Chan AM, Schrader JW, Hattori S, Nagashima K, Matsuda M. Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3. J Biol Chem. 2000 Jun 30;275(26):20020-6. PMID:10777492 doi:10.1074/jbc.M000981200
- ↑ Ohba Y, Mochizuki N, Matsuo K, Yamashita S, Nakaya M, Hashimoto Y, Hamaguchi M, Kurata T, Nagashima K, Matsuda M. Rap2 as a slowly responding molecular switch in the Rap1 signaling cascade. Mol Cell Biol. 2000 Aug;20(16):6074-83. PMID:10913189
- ↑ Ohba Y, Ikuta K, Ogura A, Matsuda J, Mochizuki N, Nagashima K, Kurokawa K, Mayer BJ, Maki K, Miyazaki J, Matsuda M. Requirement for C3G-dependent Rap1 activation for cell adhesion and embryogenesis. EMBO J. 2001 Jul 2;20(13):3333-41. PMID:11432821 doi:10.1093/emboj/20.13.3333
- ↑ Dupuy AJ, Morgan K, von Lintig FC, Shen H, Acar H, Hasz DE, Jenkins NA, Copeland NG, Boss GR, Largaespada DA. Activation of the Rap1 guanine nucleotide exchange gene, CalDAG-GEF I, in BXH-2 murine myeloid leukemia. J Biol Chem. 2001 Apr 13;276(15):11804-11. Epub 2001 Jan 22. PMID:11278453 doi:10.1074/jbc.M008970200
- ↑ Eto K, Murphy R, Kerrigan SW, Bertoni A, Stuhlmann H, Nakano T, Leavitt AD, Shattil SJ. Megakaryocytes derived from embryonic stem cells implicate CalDAG-GEFI in integrin signaling. Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12819-24. Epub 2002 Sep 18. PMID:12239348 doi:10.1073/pnas.202380099
- ↑ Crittenden JR, Bergmeier W, Zhang Y, Piffath CL, Liang Y, Wagner DD, Housman DE, Graybiel AM. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nat Med. 2004 Sep;10(9):982-6. Epub 2004 Aug 29. PMID:15334074 doi:10.1038/nm1098
- ↑ Bernardi B, Guidetti GF, Campus F, Crittenden JR, Graybiel AM, Balduini C, Torti M. The small GTPase Rap1b regulates the cross talk between platelet integrin alpha2beta1 and integrin alphaIIbbeta3. Blood. 2006 Apr 1;107(7):2728-35. Epub 2005 Dec 15. PMID:16357324 doi:2005-07-3023
- ↑ Bergmeier W, Goerge T, Wang HW, Crittenden JR, Baldwin AC, Cifuni SM, Housman DE, Graybiel AM, Wagner DD. Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III. J Clin Invest. 2007 Jun;117(6):1699-707. Epub 2007 May 10. PMID:17492052 doi:10.1172/JCI30575
- ↑ Liu Q, Berry D, Nash P, Pawson T, McGlade CJ, Li SS. Structural basis for specific binding of the Gads SH3 domain to an RxxK motif-containing SLP-76 peptide: a novel mode of peptide recognition. Mol Cell. 2003 Feb;11(2):471-81. PMID:12620234
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