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| | ==Split PH domain of PI3-kinase enhancer== | | ==Split PH domain of PI3-kinase enhancer== |
| - | <StructureSection load='2rlo' size='340' side='right' caption='[[2rlo]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | + | <StructureSection load='2rlo' size='340' side='right'caption='[[2rlo]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2rlo]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RLO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2RLO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2rlo]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RLO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2RLO FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CENTG1, AGAP2, KIAA0167 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2rlo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2rlo OCA], [http://pdbe.org/2rlo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2rlo RCSB], [http://www.ebi.ac.uk/pdbsum/2rlo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2rlo ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2rlo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2rlo OCA], [https://pdbe.org/2rlo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2rlo RCSB], [https://www.ebi.ac.uk/pdbsum/2rlo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2rlo ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/AGAP2_HUMAN AGAP2_HUMAN]] GTPase-activating protein (GAP) for ARF1 and ARF5, which also shows strong GTPase activity. Isoform 1 participates in the prevention of neuronal apoptosis by enhancing PI3 kinase activity. It aids the coupling of metabotropic glutamate receptor 1 (GRM1) to cytoplasmic PI3 kinase by interacting with Homer scaffolding proteins, and also seems to mediate anti-apoptotic effects of NGF by activating nuclear PI3 kinase. Isoform 2 does not stimulate PI3 kinase but may protect cells from apoptosis by stimulating Akt. It also regulates the adapter protein 1 (AP-1)-dependent trafficking of proteins in the endosomal system. It seems to be oncogenic. It is overexpressed in cancer cells, prevents apoptosis and promotes cancer cell invasion.<ref>PMID:12640130</ref> <ref>PMID:14761976</ref> <ref>PMID:15118108</ref> <ref>PMID:16079295</ref> | + | [https://www.uniprot.org/uniprot/AGAP2_HUMAN AGAP2_HUMAN] GTPase-activating protein (GAP) for ARF1 and ARF5, which also shows strong GTPase activity. Isoform 1 participates in the prevention of neuronal apoptosis by enhancing PI3 kinase activity. It aids the coupling of metabotropic glutamate receptor 1 (GRM1) to cytoplasmic PI3 kinase by interacting with Homer scaffolding proteins, and also seems to mediate anti-apoptotic effects of NGF by activating nuclear PI3 kinase. Isoform 2 does not stimulate PI3 kinase but may protect cells from apoptosis by stimulating Akt. It also regulates the adapter protein 1 (AP-1)-dependent trafficking of proteins in the endosomal system. It seems to be oncogenic. It is overexpressed in cancer cells, prevents apoptosis and promotes cancer cell invasion.<ref>PMID:12640130</ref> <ref>PMID:14761976</ref> <ref>PMID:15118108</ref> <ref>PMID:16079295</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Wen, W]] | + | [[Category: Large Structures]] |
| - | [[Category: Zhang, M]] | + | [[Category: Wen W]] |
| - | [[Category: Alternative splicing]] | + | [[Category: Zhang M]] |
| - | [[Category: Ank repeat]]
| + | |
| - | [[Category: Cytoplasm]]
| + | |
| - | [[Category: Gtp-binding]]
| + | |
| - | [[Category: Gtpase activation]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Nucleotide-binding]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: Oncogene]]
| + | |
| - | [[Category: Phosphorylation]]
| + | |
| - | [[Category: Polymorphism]]
| + | |
| - | [[Category: Protein transport]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| - | [[Category: Split ph domain]]
| + | |
| - | [[Category: Transport]]
| + | |
| - | [[Category: Zinc]]
| + | |
| - | [[Category: Zinc-finger]]
| + | |
| Structural highlights
Function
AGAP2_HUMAN GTPase-activating protein (GAP) for ARF1 and ARF5, which also shows strong GTPase activity. Isoform 1 participates in the prevention of neuronal apoptosis by enhancing PI3 kinase activity. It aids the coupling of metabotropic glutamate receptor 1 (GRM1) to cytoplasmic PI3 kinase by interacting with Homer scaffolding proteins, and also seems to mediate anti-apoptotic effects of NGF by activating nuclear PI3 kinase. Isoform 2 does not stimulate PI3 kinase but may protect cells from apoptosis by stimulating Akt. It also regulates the adapter protein 1 (AP-1)-dependent trafficking of proteins in the endosomal system. It seems to be oncogenic. It is overexpressed in cancer cells, prevents apoptosis and promotes cancer cell invasion.[1] [2] [3] [4]
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
Cytoplasm-nucleus shuttling of phosphoinositol 3-kinase enhancer (PIKE) is known to correlate directly with its cellular functions. However, the molecular mechanism governing this shuttling is not known. In this work, we demonstrate that PIKE is a new member of split pleckstrin homology (PH) domain-containing proteins. The structure solved in this work reveals that the PIKE PH domain is split into halves by a positively charged nuclear localization sequence. The PIKE PH domain binds to the head groups of di- and triphosphoinositides with similar affinities. Lipid membrane binding of the PIKE PH domain is further enhanced by the positively charged nuclear localization sequence, which is juxtaposed to the phosphoinositide head group-binding pocket of the domain. We demonstrate that the cytoplasmic-nuclear shuttling of PIKE is dynamically regulated by the balancing actions of the lipid-binding property of both the split PH domain and the nuclear targeting function of its nuclear localization sequence.
Split pleckstrin homology domain-mediated cytoplasmic-nuclear localization of PI3-kinase enhancer GTPase.,Yan J, Wen W, Chan LN, Zhang M J Mol Biol. 2008 Apr 25;378(2):425-35. Epub 2008 Mar 4. PMID:18371979[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Xia C, Ma W, Stafford LJ, Liu C, Gong L, Martin JF, Liu M. GGAPs, a new family of bifunctional GTP-binding and GTPase-activating proteins. Mol Cell Biol. 2003 Apr;23(7):2476-88. PMID:12640130
- ↑ Ahn JY, Rong R, Kroll TG, Van Meir EG, Snyder SH, Ye K. PIKE (phosphatidylinositol 3-kinase enhancer)-A GTPase stimulates Akt activity and mediates cellular invasion. J Biol Chem. 2004 Apr 16;279(16):16441-51. Epub 2004 Feb 3. PMID:14761976 doi:http://dx.doi.org/10.1074/jbc.M312175200
- ↑ Ahn JY, Hu Y, Kroll TG, Allard P, Ye K. PIKE-A is amplified in human cancers and prevents apoptosis by up-regulating Akt. Proc Natl Acad Sci U S A. 2004 May 4;101(18):6993-8. Epub 2004 Apr 26. PMID:15118108 doi:http://dx.doi.org/10.1073/pnas.0400921101
- ↑ Nie Z, Fei J, Premont RT, Randazzo PA. The Arf GAPs AGAP1 and AGAP2 distinguish between the adaptor protein complexes AP-1 and AP-3. J Cell Sci. 2005 Aug 1;118(Pt 15):3555-66. PMID:16079295 doi:http://dx.doi.org/10.1242/jcs.02486
- ↑ Yan J, Wen W, Chan LN, Zhang M. Split pleckstrin homology domain-mediated cytoplasmic-nuclear localization of PI3-kinase enhancer GTPase. J Mol Biol. 2008 Apr 25;378(2):425-35. Epub 2008 Mar 4. PMID:18371979 doi:10.1016/j.jmb.2008.02.052
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