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| | ==Crystal structure of the KRIT1/CCM1 FERM domain in complex with the heart of glass (HEG1) cytoplasmic tail== | | ==Crystal structure of the KRIT1/CCM1 FERM domain in complex with the heart of glass (HEG1) cytoplasmic tail== |
| - | <StructureSection load='3u7d' size='340' side='right' caption='[[3u7d]], [[Resolution|resolution]] 2.49Å' scene=''> | + | <StructureSection load='3u7d' size='340' side='right'caption='[[3u7d]], [[Resolution|resolution]] 2.49Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3u7d]] is a 4 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=3U7D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3U7D FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3u7d]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3U7D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3U7D FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CCM1, Cerebral cavernous malformations 1 protein, Krev interaction trapped protein 1 or CCM1, KRIT1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CCM1, Cerebral cavernous malformations 1 protein, Krev interaction trapped protein 1 or CCM1, KRIT1 ([https://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3u7d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3u7d OCA], [http://pdbe.org/3u7d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3u7d RCSB], [http://www.ebi.ac.uk/pdbsum/3u7d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3u7d 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=3u7d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3u7d OCA], [https://pdbe.org/3u7d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3u7d RCSB], [https://www.ebi.ac.uk/pdbsum/3u7d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3u7d ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/KRIT1_HUMAN KRIT1_HUMAN]] Hereditary cerebral cavernous malformation. Cerebral cavernous malformations 1 (CCM1) [MIM:[http://omim.org/entry/116860 116860]]: A congenital vascular anomaly of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:12172908</ref> | + | [[https://www.uniprot.org/uniprot/KRIT1_HUMAN KRIT1_HUMAN]] Hereditary cerebral cavernous malformation. Cerebral cavernous malformations 1 (CCM1) [MIM:[https://omim.org/entry/116860 116860]]: A congenital vascular anomaly of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:12172908</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/KRIT1_HUMAN KRIT1_HUMAN]] Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity (By similarity). Negative regulator of angiogenesis. Inhibits endothelial proliferation, apoptosis, migration, lumen formation and sprouting angiogenesis in primary endothelial cells. Promotes AKT phosphorylation in a NOTCH-dependent and independent manner, and inhibits EKR1/2 phosphorylation indirectly through activation of the DELTA-NOTCH cascade. Acts in concert with CDH5 to establish and maintain correct endothelial cell polarity and vascular lumen and these effects are mediated by recruitment and activation of the Par polarity complex and RAP1B. Required for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction, and cell junction stabilization. Plays a role in integrin signaling via its interaction with ITGB1BP1; this prevents the interaction between ITGB1 and ITGB1BP1. Plays an important role in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent oxidative cellular damage. Regulates the homeostasis of intracellular ROS through an antioxidant pathway involving FOXO1 and SOD2. Facilitates the down-regulation of cyclin-D1 (CCND1) levels required for cell transition from proliferative growth to quiescence by preventing the accumulation of intracellular ROS through the modulation of FOXO1 and SOD2 levels.<ref>PMID:20332120</ref> <ref>PMID:20668652</ref> <ref>PMID:20616044</ref> <ref>PMID:21633110</ref> [REFERENCE:17] [[http://www.uniprot.org/uniprot/HEG1_HUMAN HEG1_HUMAN]] Receptor 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). | + | [[https://www.uniprot.org/uniprot/KRIT1_HUMAN KRIT1_HUMAN]] Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity (By similarity). Negative regulator of angiogenesis. Inhibits endothelial proliferation, apoptosis, migration, lumen formation and sprouting angiogenesis in primary endothelial cells. Promotes AKT phosphorylation in a NOTCH-dependent and independent manner, and inhibits EKR1/2 phosphorylation indirectly through activation of the DELTA-NOTCH cascade. Acts in concert with CDH5 to establish and maintain correct endothelial cell polarity and vascular lumen and these effects are mediated by recruitment and activation of the Par polarity complex and RAP1B. Required for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction, and cell junction stabilization. Plays a role in integrin signaling via its interaction with ITGB1BP1; this prevents the interaction between ITGB1 and ITGB1BP1. Plays an important role in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent oxidative cellular damage. Regulates the homeostasis of intracellular ROS through an antioxidant pathway involving FOXO1 and SOD2. Facilitates the down-regulation of cyclin-D1 (CCND1) levels required for cell transition from proliferative growth to quiescence by preventing the accumulation of intracellular ROS through the modulation of FOXO1 and SOD2 levels.<ref>PMID:20332120</ref> <ref>PMID:20668652</ref> <ref>PMID:20616044</ref> <ref>PMID:21633110</ref> [REFERENCE:17] [[https://www.uniprot.org/uniprot/HEG1_HUMAN HEG1_HUMAN]] Receptor 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). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Human]] | | [[Category: Human]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Assembly, Dynamics and Evolution of Cell-Cell and Cell-Matrix Adhesions CELLMAT]] | | [[Category: Assembly, Dynamics and Evolution of Cell-Cell and Cell-Matrix Adhesions CELLMAT]] |
| | [[Category: Gingras, A R]] | | [[Category: Gingras, A R]] |
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| | [[Category: Psi-biology]] | | [[Category: Psi-biology]] |
| | [[Category: Rap1 effector]] | | [[Category: Rap1 effector]] |
| | + | [[Category: Structural genomic]] |
| Structural highlights
3u7d is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Gene: | CCM1, Cerebral cavernous malformations 1 protein, Krev interaction trapped protein 1 or CCM1, KRIT1 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[KRIT1_HUMAN] Hereditary cerebral cavernous malformation. Cerebral cavernous malformations 1 (CCM1) [MIM:116860]: A congenital vascular anomaly of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters. Note=The disease is caused by mutations affecting the gene represented in this entry.[1]
Function
[KRIT1_HUMAN] Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity (By similarity). Negative regulator of angiogenesis. Inhibits endothelial proliferation, apoptosis, migration, lumen formation and sprouting angiogenesis in primary endothelial cells. Promotes AKT phosphorylation in a NOTCH-dependent and independent manner, and inhibits EKR1/2 phosphorylation indirectly through activation of the DELTA-NOTCH cascade. Acts in concert with CDH5 to establish and maintain correct endothelial cell polarity and vascular lumen and these effects are mediated by recruitment and activation of the Par polarity complex and RAP1B. Required for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction, and cell junction stabilization. Plays a role in integrin signaling via its interaction with ITGB1BP1; this prevents the interaction between ITGB1 and ITGB1BP1. Plays an important role in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent oxidative cellular damage. Regulates the homeostasis of intracellular ROS through an antioxidant pathway involving FOXO1 and SOD2. Facilitates the down-regulation of cyclin-D1 (CCND1) levels required for cell transition from proliferative growth to quiescence by preventing the accumulation of intracellular ROS through the modulation of FOXO1 and SOD2 levels.[2] [3] [4] [5] [REFERENCE:17] [HEG1_HUMAN] Receptor 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).
Publication Abstract from PubMed
The products of genes that cause cerebral cavernous malformations (CCM1/KRIT1, CCM2, and CCM3) physically interact. CCM1/KRIT1 links this complex to endothelial cell (EC) junctions and maintains junctional integrity in part by inhibiting RhoA. Heart of glass (HEG1), a transmembrane protein, associates with KRIT1. In this paper, we show that the KRIT1 band 4.1, ezrin, radixin, and moesin (FERM) domain bound the HEG1 C terminus (K(d) = 1.2 microM) and solved the structure of this assembly. The KRIT1 F1 and F3 subdomain interface formed a hydrophobic groove that binds HEG1(Tyr(1,380)-Phe(1,381)), thus defining a new mode of FERM domain-membrane protein interaction. This structure enabled design of KRIT1(L717,721A), which exhibited a >100-fold reduction in HEG1 affinity. Although well folded and expressed, KRIT1(L717,721A) failed to target to EC junctions or complement the effects of KRIT1 depletion on zebrafish cardiovascular development or Rho kinase activation in EC. These data establish that this novel FERM-membrane protein interaction anchors CCM1/KRIT1 at EC junctions to support cardiovascular development.
Structural basis of the junctional anchorage of the cerebral cavernous malformations complex.,Gingras AR, Liu JJ, Ginsberg MH J Cell Biol. 2012 Oct 1;199(1):39-48. doi: 10.1083/jcb.201205109. Epub 2012 Sep, 24. PMID:23007647[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kehrer-Sawatzki H, Wilda M, Braun VM, Richter HP, Hameister H. Mutation and expression analysis of the KRIT1 gene associated with cerebral cavernous malformations (CCM1). Acta Neuropathol. 2002 Sep;104(3):231-40. Epub 2002 Jun 26. PMID:12172908 doi:10.1007/s00401-002-0552-6
- ↑ Lampugnani MG, Orsenigo F, Rudini N, Maddaluno L, Boulday G, Chapon F, Dejana E. CCM1 regulates vascular-lumen organization by inducing endothelial polarity. J Cell Sci. 2010 Apr 1;123(Pt 7):1073-80. doi: 10.1242/jcs.059329. PMID:20332120 doi:10.1242/jcs.059329
- ↑ Goitre L, Balzac F, Degani S, Degan P, Marchi S, Pinton P, Retta SF. KRIT1 regulates the homeostasis of intracellular reactive oxygen species. PLoS One. 2010 Jul 26;5(7):e11786. doi: 10.1371/journal.pone.0011786. PMID:20668652 doi:10.1371/journal.pone.0011786
- ↑ Wustehube J, Bartol A, Liebler SS, Brutsch R, Zhu Y, Felbor U, Sure U, Augustin HG, Fischer A. Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling. Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12640-5. doi:, 10.1073/pnas.1000132107. Epub 2010 Jun 24. PMID:20616044 doi:10.1073/pnas.1000132107
- ↑ Liu JJ, Stockton RA, Gingras AR, Ablooglu AJ, Han J, Bobkov AA, Ginsberg MH. A mechanism of Rap1-induced stabilization of endothelial cell--cell junctions. Mol Biol Cell. 2011 Jul 15;22(14):2509-19. doi: 10.1091/mbc.E11-02-0157. Epub, 2011 Jun 1. PMID:21633110 doi:10.1091/mbc.E11-02-0157
- ↑ Gingras AR, Liu JJ, Ginsberg MH. Structural basis of the junctional anchorage of the cerebral cavernous malformations complex. J Cell Biol. 2012 Oct 1;199(1):39-48. doi: 10.1083/jcb.201205109. Epub 2012 Sep, 24. PMID:23007647 doi:http://dx.doi.org/10.1083/jcb.201205109
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