2ahx
From Proteopedia
(Difference between revisions)
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==Crystal structure of ErbB4/HER4 extracellular domain== | ==Crystal structure of ErbB4/HER4 extracellular domain== | ||
| - | <StructureSection load='2ahx' size='340' side='right'caption='[[2ahx]]' scene=''> | + | <StructureSection load='2ahx' size='340' side='right'caption='[[2ahx]], [[Resolution|resolution]] 2.40Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AHX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2AHX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2ahx]] 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=2AHX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2AHX FirstGlance]. <br> |
| - | </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=2ahx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ahx OCA], [https://pdbe.org/2ahx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ahx RCSB], [https://www.ebi.ac.uk/pdbsum/2ahx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ahx ProSAT]</span></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]] 2.396Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=YT3:YTTRIUM+(III)+ION'>YT3</scene></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=2ahx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ahx OCA], [https://pdbe.org/2ahx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ahx RCSB], [https://www.ebi.ac.uk/pdbsum/2ahx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ahx ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/ERBB4_HUMAN ERBB4_HUMAN] Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis.<ref>PMID:8383326</ref> <ref>PMID:9334263</ref> <ref>PMID:8617750</ref> <ref>PMID:9135143</ref> <ref>PMID:9168115</ref> <ref>PMID:10358079</ref> <ref>PMID:10353604</ref> <ref>PMID:10348342</ref> <ref>PMID:10722704</ref> <ref>PMID:10867024</ref> <ref>PMID:11178955</ref> <ref>PMID:11390655</ref> <ref>PMID:12807903</ref> <ref>PMID:15534001</ref> <ref>PMID:15746097</ref> <ref>PMID:16778220</ref> <ref>PMID:16251361</ref> <ref>PMID:16837552</ref> <ref>PMID:17120616</ref> <ref>PMID:17638867</ref> <ref>PMID:17486069</ref> <ref>PMID:19098003</ref> <ref>PMID:20858735</ref> <ref>PMID:21811097</ref> | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2ahx ConSurf]. | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2ahx ConSurf]. | ||
<div style="clear:both"></div> | <div style="clear:both"></div> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The human ErbB family of receptor tyrosine kinases comprises the epidermal growth factor receptor (EGFR/ErbB1/HER1), ErbB2 (HER2/Neu), ErbB3 (HER3), and ErbB4 (HER4). ErbBs play fundamental roles in cell growth and differentiation events in embryonic and adult tissues, and inappropriate ErbB activity has been implicated in several human cancers. We report here the 2.4 A crystal structure of the extracellular region of human ErbB4 in the absence of ligand and show that it adopts a tethered conformation similar to inactive forms of ErbB1 and ErbB3. This structure completes the gallery of unliganded ErbB receptors and demonstrates that all human ligand-binding ErbBs adopt the autoinhibited conformation. We also show that the binding of neuregulin-1beta to ErbB4 and ErbB3 and the binding of betacellulin to both ErbB4 and ErbB1 does not decrease at low pH, unlike the binding of epidermal growth factor and transforming growth factor-alpha to ErbB1. These results indicate an important role for ligand in determining pH-dependent binding and may explain different responses observed when the same ErbB receptor is stimulated by different ligands. | ||
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| + | The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand.,Bouyain S, Longo PA, Li S, Ferguson KM, Leahy DJ Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15024-9. Epub 2005 Oct 3. PMID:16203964<ref>PMID:16203964</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 2ahx" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Bouyain S]] | [[Category: Bouyain S]] | ||
Revision as of 08:18, 15 May 2024
Crystal structure of ErbB4/HER4 extracellular domain
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Categories: Homo sapiens | Large Structures | Bouyain S | Ferguson KM | Leahy DJ | Li S | Longo PA
