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==Crystal structure of the Grb14 BPS region in complex with the insulin receptor tyrosine kinase==
==Crystal structure of the Grb14 BPS region in complex with the insulin receptor tyrosine kinase==
<StructureSection load='2auh' size='340' side='right' caption='[[2auh]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
<StructureSection load='2auh' size='340' side='right'caption='[[2auh]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[2auh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AUH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2AUH FirstGlance]. <br>
<table><tr><td colspan='2'>[[2auh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AUH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2AUH FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.2&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">INSR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GRB14 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=2auh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2auh OCA], [https://pdbe.org/2auh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2auh RCSB], [https://www.ebi.ac.uk/pdbsum/2auh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2auh ProSAT]</span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </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=2auh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2auh OCA], [http://pdbe.org/2auh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2auh RCSB], [http://www.ebi.ac.uk/pdbsum/2auh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2auh ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Defects in INSR are the cause of Rabson-Mendenhall syndrome (RMS) [MIM:[http://omim.org/entry/262190 262190]]; also known as Mendenhall syndrome. RMS is a severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive.<ref>PMID:2121734</ref> <ref>PMID:2365819</ref> <ref>PMID:8314008</ref> <ref>PMID:10443650</ref> <ref>PMID:12023989</ref> <ref>PMID:17201797</ref>  Defects in INSR are the cause of leprechaunism (LEPRCH) [MIM:[http://omim.org/entry/246200 246200]]; also known as Donohue syndrome. Leprechaunism represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive.<ref>PMID:2365819</ref> <ref>PMID:12023989</ref> <ref>PMID:2834824</ref> <ref>PMID:2479553</ref> <ref>PMID:1607067</ref> <ref>PMID:1730625</ref> <ref>PMID:8326490</ref> <ref>PMID:8419945</ref> <ref>PMID:8188715</ref> <ref>PMID:7815442</ref> <ref>PMID:7538143</ref> <ref>PMID:8636294</ref> <ref>PMID:9299395</ref> <ref>PMID:9249867</ref> <ref>PMID:9703342</ref> <ref>PMID:12538626</ref> <ref>PMID:12970295</ref>  Defects in INSR may be associated with noninsulin-dependent diabetes mellitus (NIDDM) [MIM:[http://omim.org/entry/125853 125853]]; also known as diabetes mellitus type 2.<ref>PMID:1607076</ref> <ref>PMID:1470163</ref> <ref>PMID:7657032</ref>  Defects in INSR are the cause of familial hyperinsulinemic hypoglycemia type 5 (HHF5) [MIM:[http://omim.org/entry/609968 609968]]. Familial hyperinsulinemic hypoglycemia [MIM:[http://omim.org/entry/256450 256450]], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels.<ref>PMID:15161766</ref>  Defects in INSR are the cause of insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:[http://omim.org/entry/610549 610549]]. This syndrome is characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor.
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.<ref>PMID:8257688</ref> <ref>PMID:8452530</ref> <ref>PMID:8276809</ref> <ref>PMID:9428692</ref> <ref>PMID:10207053</ref> <ref>PMID:12138094</ref> <ref>PMID:16314505</ref> <ref>PMID:16831875</ref>  [[http://www.uniprot.org/uniprot/GRB14_HUMAN GRB14_HUMAN]] Adapter protein which modulates coupling of cell surface receptor kinases with specific signaling pathways. Binds to, and suppresses signals from, the activated insulin receptor (INSR). Potent inhibitor of insulin-stimulated MAPK3 phosphorylation. Plays a critical role regulating PDPK1 membrane translocation in response to insulin stimulation and serves as an adapter protein to recruit PDPK1 to activated insulin receptor, thus promoting PKB/AKT1 phosphorylation and transduction of the insulin signal.<ref>PMID:15210700</ref> <ref>PMID:19648926</ref>
[https://www.uniprot.org/uniprot/GRB14_HUMAN GRB14_HUMAN] Adapter protein which modulates coupling of cell surface receptor kinases with specific signaling pathways. Binds to, and suppresses signals from, the activated insulin receptor (INSR). Potent inhibitor of insulin-stimulated MAPK3 phosphorylation. Plays a critical role regulating PDPK1 membrane translocation in response to insulin stimulation and serves as an adapter protein to recruit PDPK1 to activated insulin receptor, thus promoting PKB/AKT1 phosphorylation and transduction of the insulin signal.<ref>PMID:15210700</ref> <ref>PMID:19648926</ref>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/au/2auh_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/au/2auh_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
   </jmolCheckbox>
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==See Also==
==See Also==
*[[Growth factor receptor-bound protein|Growth factor receptor-bound protein]]
*[[Growth factor receptor-bound proteins 3D structures|Growth factor receptor-bound proteins 3D structures]]
*[[Insulin receptor|Insulin receptor]]
*[[Insulin receptor 3D structures|Insulin receptor 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Transferase]]
[[Category: Large Structures]]
[[Category: Daly, R J]]
[[Category: Daly RJ]]
[[Category: Depetris, R S]]
[[Category: Depetris RS]]
[[Category: Gimpelevich, I]]
[[Category: Gimpelevich I]]
[[Category: Holt, L J]]
[[Category: Holt LJ]]
[[Category: Hu, J]]
[[Category: Hu J]]
[[Category: Hubbard, S R]]
[[Category: Hubbard SR]]
[[Category: Bps region]]
[[Category: Transferase-signaling protein complex]]
[[Category: Tyrosine kinase]]

Latest revision as of 03:47, 21 November 2024

Crystal structure of the Grb14 BPS region in complex with the insulin receptor tyrosine kinaseCrystal structure of the Grb14 BPS region in complex with the insulin receptor tyrosine kinase

Structural highlights

2auh is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.2Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GRB14_HUMAN Adapter protein which modulates coupling of cell surface receptor kinases with specific signaling pathways. Binds to, and suppresses signals from, the activated insulin receptor (INSR). Potent inhibitor of insulin-stimulated MAPK3 phosphorylation. Plays a critical role regulating PDPK1 membrane translocation in response to insulin stimulation and serves as an adapter protein to recruit PDPK1 to activated insulin receptor, thus promoting PKB/AKT1 phosphorylation and transduction of the insulin signal.[1] [2]

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

Grb14, a member of the Grb7 adaptor protein family, possesses a pleckstrin homology (PH) domain, a C-terminal Src homology-2 (SH2) domain, and an intervening stretch of approximately 45 residues known as the BPS region, which is unique to this adaptor family. Previous studies have demonstrated that Grb14 is a tissue-specific negative regulator of insulin receptor signaling and that inhibition is mediated by the BPS region. We have determined the crystal structure of the Grb14 BPS region in complex with the tyrosine kinase domain of the insulin receptor. The structure reveals that the N-terminal portion of the BPS region binds as a pseudosubstrate inhibitor in the substrate peptide binding groove of the kinase. Together with the crystal structure of the SH2 domain, we present a model for the interaction of Grb14 with the insulin receptor, which indicates how Grb14 functions as a selective protein inhibitor of insulin signaling.

Structural basis for inhibition of the insulin receptor by the adaptor protein Grb14.,Depetris RS, Hu J, Gimpelevich I, Holt LJ, Daly RJ, Hubbard SR Mol Cell. 2005 Oct 28;20(2):325-33. PMID:16246733[3]

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

See Also

References

  1. ↑ King CC, Newton AC. The adaptor protein Grb14 regulates the localization of 3-phosphoinositide-dependent kinase-1. J Biol Chem. 2004 Sep 3;279(36):37518-27. Epub 2004 Jun 21. PMID:15210700 doi:10.1074/jbc.M405340200
  2. ↑ Depetris RS, Wu J, Hubbard SR. Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14. Nat Struct Mol Biol. 2009 Aug;16(8):833-9. Epub 2009 Aug 2. PMID:19648926 doi:10.1038/nsmb.1642
  3. ↑ Depetris RS, Hu J, Gimpelevich I, Holt LJ, Daly RJ, Hubbard SR. Structural basis for inhibition of the insulin receptor by the adaptor protein Grb14. Mol Cell. 2005 Oct 28;20(2):325-33. PMID:16246733 doi:10.1016/j.molcel.2005.09.001

2auh, resolution 3.20Å

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