| Structural highlights
1uti is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Related: | 1h3h, 1oeb |
| Activity: | Transferase, with EC number 2.7.11.8, 2.7.11.9, 2.7.11.10, 2.7.11.11, 2.7.11.12, 2.7.11.13, 2.7.11.21, 2.7.11.22, 2.7.11.24, 2.7.11.25, 2.7.11.30 and 2.7.12.1 2.7.11.1, 2.7.11.8, 2.7.11.9, 2.7.11.10, 2.7.11.11, 2.7.11.12, 2.7.11.13, 2.7.11.21, 2.7.11.22, 2.7.11.24, 2.7.11.25, 2.7.11.30 and 2.7.12.1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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] [M4K1_MOUSE] May play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. May play a role in hematopoietic lineage decisions and growth regulation.[10]
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
Hematopoietic progenitor kinase 1 (HPK1) is implicated in signaling downstream of the T cell receptor. Its non-catalytic, C-terminal half contains several prolinerich motifs, which have been shown to interact with different SH3 domain-containing adaptor proteins in vitro. One of these, Mona/Gads, was also shown to bind HPK1 in mouse T cells in vivo. The region of HPK1 that binds to the Mona/Gads C-terminal SH3 domain has been mapped and shows only very limited similarity to a recently identified high affinity binding motif in SLP-76, another T-cell adaptor. Using isothermal titration calorimetry and x-ray crystallography, the binding of the HPK1 motif to Mona/Gads SH3C has now been characterized in molecular detail. The results indicate that although charge interactions through an RXXK motif are essential for complex formation, a PXXP motif in HPK1 strongly complements binding. This unexpected binding mode therefore differs considerably from the previously described interaction of Mona/Gads SH3C with SLP-76. The crystal structure of the complex highlights the great versatility of SH3 domains, which allows interactions with very different proteins. This currently limits our ability to categorize SH3 binding properties by simple rules.
Mona/Gads SH3C binding to hematopoietic progenitor kinase 1 (HPK1) combines an atypical SH3 binding motif, R/KXXK, with a classical PXXP motif embedded in a polyproline type II (PPII) helix.,Lewitzky M, Harkiolaki M, Domart MC, Jones EY, Feller SM J Biol Chem. 2004 Jul 2;279(27):28724-32. Epub 2004 Apr 20. PMID:15100220[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Kiefer F, Tibbles LA, Anafi M, Janssen A, Zanke BW, Lassam N, Pawson T, Woodgett JR, Iscove NN. HPK1, a hematopoietic protein kinase activating the SAPK/JNK pathway. EMBO J. 1996 Dec 16;15(24):7013-25. PMID:9003777
- ↑ Lewitzky M, Harkiolaki M, Domart MC, Jones EY, Feller SM. Mona/Gads SH3C binding to hematopoietic progenitor kinase 1 (HPK1) combines an atypical SH3 binding motif, R/KXXK, with a classical PXXP motif embedded in a polyproline type II (PPII) helix. J Biol Chem. 2004 Jul 2;279(27):28724-32. Epub 2004 Apr 20. PMID:15100220 doi:10.1074/jbc.M402745200
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