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2v1y

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Revision as of 08:53, 12 September 2018

Structure of a phosphoinositide 3-kinase alpha adaptor-binding domain (ABD) in a complex with the iSH2 domain from p85 alpha

Structural highlights

2v1y is a 2 chain structure with sequence from Bovin and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:
Related:	1a0n, 1azg, 1h9o, 1pbw, 1pht, 1pic, 1pks, 1pkt, 2iug, 2iuh, 2iui
Activity:	Phosphatidylinositol-4,5-bisphosphate 3-kinase, with EC number 2.7.1.153
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PK3CA_BOVIN] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway (By similarity). Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS.^[1] ^[2] [P85A_HUMAN] Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling.^[3] ^[4] ^[5]

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

Many human cancers involve up-regulation of the phosphoinositide 3-kinase PI3Kalpha, with oncogenic mutations identified in both the p110alpha catalytic and the p85alpha regulatory subunits. We used crystallographic and biochemical approaches to gain insight into activating mutations in two noncatalytic p110alpha domains-the adaptor-binding and the helical domains. A structure of the adaptor-binding domain of p110alpha in a complex with the p85alpha inter-Src homology 2 (inter-SH2) domain shows that oncogenic mutations in the adaptor-binding domain are not at the inter-SH2 interface but in a polar surface patch that is a plausible docking site for other domains in the holo p110/p85 complex. We also examined helical domain mutations and found that the Glu545 to Lys545 (E545K) oncogenic mutant disrupts an inhibitory charge-charge interaction with the p85 N-terminal SH2 domain. These studies extend our understanding of the architecture of PI3Ks and provide insight into how two classes of mutations that cause a gain in function can lead to cancer.

Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit.,Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, Schneidman-Duhovny D, Wolfson HJ, Backer JM, Williams RL Science. 2007 Jul 13;317(5835):239-42. PMID:17626883^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Foukas LC, Shepherd PR. eIF4E binding protein 1 and H-Ras are novel substrates for the protein kinase activity of class-I phosphoinositide 3-kinase. Biochem Biophys Res Commun. 2004 Jun 25;319(2):541-9. PMID:15178440 doi:http://dx.doi.org/10.1016/j.bbrc.2004.04.191
↑ Foukas LC, Beeton CA, Jensen J, Phillips WA, Shepherd PR. Regulation of phosphoinositide 3-kinase by its intrinsic serine kinase activity in vivo. Mol Cell Biol. 2004 Feb;24(3):966-75. PMID:14729945
↑ Vainikka S, Joukov V, Wennstrom S, Bergman M, Pelicci PG, Alitalo K. Signal transduction by fibroblast growth factor receptor-4 (FGFR-4). Comparison with FGFR-1. J Biol Chem. 1994 Jul 15;269(28):18320-6. PMID:7518429
↑ Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, Schneidman-Duhovny D, Wolfson HJ, Backer JM, Williams RL. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science. 2007 Jul 13;317(5835):239-42. PMID:17626883 doi:317/5835/239
↑ Mandelker D, Gabelli SB, Schmidt-Kittler O, Zhu J, Cheong I, Huang CH, Kinzler KW, Vogelstein B, Amzel LM. A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane. Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):16996-7001. Epub 2009 Sep 23. PMID:19805105
↑ Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, Schneidman-Duhovny D, Wolfson HJ, Backer JM, Williams RL. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science. 2007 Jul 13;317(5835):239-42. PMID:17626883 doi:317/5835/239

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2v1y"

@@ Line 1: / Line 1: @@
-==STRUCTURE OF A PHOSPHOINOSITIDE 3-KINASE ALPHA ADAPTOR-BINDING DOMAIN (ABD) IN A COMPLEX WITH THE ISH2 DOMAIN FROM P85 ALPHA==
+==Structure of a phosphoinositide 3-kinase alpha adaptor-binding domain (ABD) in a complex with the iSH2 domain from p85 alpha==
 <StructureSection load='2v1y' size='340' side='right' caption='[[2v1y]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1a0n|1a0n]], [[1azg|1azg]], [[1h9o|1h9o]], [[1pbw|1pbw]], [[1pht|1pht]], [[1pic|1pic]], [[1pks|1pks]], [[1pkt|1pkt]], [[2iug|2iug]], [[2iuh|2iuh]], [[2iui|2iui]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </span></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=2v1y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2v1y OCA], [http://pdbe.org/2v1y PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2v1y RCSB], [http://www.ebi.ac.uk/pdbsum/2v1y PDBsum]</span></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=2v1y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2v1y OCA], [http://pdbe.org/2v1y PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2v1y RCSB], [http://www.ebi.ac.uk/pdbsum/2v1y PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2v1y ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 14: / Line 15: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/v1/2v1y_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/v1/2v1y_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>

2v1y

From Proteopedia

Revision as of 08:53, 12 September 2018

Structure of a phosphoinositide 3-kinase alpha adaptor-binding domain (ABD) in a complex with the iSH2 domain from p85 alpha

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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