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| | ==CCM2 HHD in complex with MEKK3 NPB1== | | ==CCM2 HHD in complex with MEKK3 NPB1== |
| - | <StructureSection load='4y5o' size='340' side='right' caption='[[4y5o]], [[Resolution|resolution]] 2.35Å' scene=''> | + | <StructureSection load='4y5o' size='340' side='right'caption='[[4y5o]], [[Resolution|resolution]] 2.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4y5o]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y5O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y5O FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4y5o]] 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=4Y5O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Y5O FirstGlance]. <br> |
| - | </td></tr><tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] </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]] 2.35Å</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=4y5o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y5o OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4y5o RCSB], [http://www.ebi.ac.uk/pdbsum/4y5o PDBsum]</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=4y5o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y5o OCA], [https://pdbe.org/4y5o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4y5o RCSB], [https://www.ebi.ac.uk/pdbsum/4y5o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4y5o ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/CCM2_HUMAN CCM2_HUMAN]] Hereditary cerebral cavernous malformation. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/CCM2_HUMAN CCM2_HUMAN] Hereditary cerebral cavernous malformation. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CCM2_HUMAN CCM2_HUMAN]] Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity. May act through the stabilization of endothelial cell junctions (By similarity). May function as a scaffold protein for MAP2K3-MAP3K3 signaling. Seems to play a major role in the modulation of MAP3K3-dependent p38 activation induced by hyperosmotic shock (By similarity). [[http://www.uniprot.org/uniprot/M3K3_HUMAN M3K3_HUMAN]] Component of a protein kinase signal transduction cascade. Mediates activation of the NF-kappa-B, AP1 and DDIT3 transcriptional regulators.<ref>PMID:9006902</ref> <ref>PMID:12912994</ref> <ref>PMID:14661019</ref> <ref>PMID:14743216</ref> | + | [https://www.uniprot.org/uniprot/CCM2_HUMAN CCM2_HUMAN] Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity. May act through the stabilization of endothelial cell junctions (By similarity). May function as a scaffold protein for MAP2K3-MAP3K3 signaling. Seems to play a major role in the modulation of MAP3K3-dependent p38 activation induced by hyperosmotic shock (By similarity). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4y5o" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Mitogen-activated protein kinase kinase kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Boggon, T J]] | + | [[Category: Large Structures]] |
| - | [[Category: Fisher, O S]] | + | [[Category: Boggon TJ]] |
| - | [[Category: Complex]] | + | [[Category: Fisher OS]] |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Scaffold]]
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| - | [[Category: Transferase]]
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| Structural highlights
Disease
CCM2_HUMAN Hereditary cerebral cavernous malformation. The disease is caused by mutations affecting the gene represented in this entry.
Function
CCM2_HUMAN Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity. May act through the stabilization of endothelial cell junctions (By similarity). May function as a scaffold protein for MAP2K3-MAP3K3 signaling. Seems to play a major role in the modulation of MAP3K3-dependent p38 activation induced by hyperosmotic shock (By similarity).
Publication Abstract from PubMed
Cerebral cavernous malformations 2 (CCM2) loss is associated with the familial form of CCM disease. The protein kinase MEKK3 (MAP3K3) is essential for embryonic angiogenesis in mice and interacts physically with CCM2, but how this interaction is mediated and its relevance to cerebral vasculature are unknown. Here we report that Mekk3 plays an intrinsic role in embryonic vascular development. Inducible endothelial Mekk3 knockout in neonatal mice is lethal due to multiple intracranial haemorrhages and brain blood vessels leakage. We discover direct interaction between CCM2 harmonin homology domain (HHD) and the N terminus of MEKK3, and determine a 2.35 A cocrystal structure. We find Mekk3 deficiency impairs neurovascular integrity, which is partially dependent on Rho-ROCK signalling, and that disruption of MEKK3:CCM2 interaction leads to similar neurovascular leakage. We conclude that CCM2:MEKK3-mediated regulation of Rho signalling is required for maintenance of neurovascular integrity, unravelling a mechanism by which CCM2 loss leads to disease.
Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex.,Fisher OS, Deng H, Liu D, Zhang Y, Wei R, Deng Y, Zhang F, Louvi A, Turk BE, Boggon TJ, Su B Nat Commun. 2015 Aug 3;6:7937. doi: 10.1038/ncomms8937. PMID:26235885[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Fisher OS, Deng H, Liu D, Zhang Y, Wei R, Deng Y, Zhang F, Louvi A, Turk BE, Boggon TJ, Su B. Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex. Nat Commun. 2015 Aug 3;6:7937. doi: 10.1038/ncomms8937. PMID:26235885 doi:http://dx.doi.org/10.1038/ncomms8937
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