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4dx8

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Revision as of 06:58, 2 September 2020

ICAP1 in complex with KRIT1 N-terminus

Structural highlights

4dx8 is a 8 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	4dx9, 4dxa
Gene:	ICAP1, Integrin cytoplasmic domain-associated protein 1 (ICAP1), ITGB1BP1 (HUMAN), CCM1, Krev interaction trapped protein 1 (KRIT1), 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

[ITBP1_HUMAN] Regulates integrin signaling by binding to the ITGB1 cytoplasmic tail and preventing the activation of integrin alpha-5/beta-1 (heterodimer of ITGA5 and ITGB1) by talin or FERMT1. May play a role in the recruitment of ITGB1 to focal contacts during integrin-dependent cell adhesion.[REFERENCE:8] [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]

Publication Abstract from PubMed

KRIT1 (Krev/Rap1 Interaction Trapped-1) mutations are observed in approximately 40% of autosomal-dominant cerebral cavernous malformations (CCMs), a disease occurring in up to 0.5% of the population. We show that KRIT1 functions as a switch for beta1 integrin activation by antagonizing ICAP1 (Integrin Cytoplasmic Associated Protein-1)-mediated modulation of "inside-out" activation. We present cocrystal structures of KRIT1 with ICAP1 and ICAP1 with integrin beta1 cytoplasmic tail to 2.54 and 3.0 A resolution (the resolutions at which I/sigmaI = 2 are 2.75 and 3.0 A, respectively). We find that KRIT1 binds ICAP1 by a bidentate surface, that KRIT1 directly competes with integrin beta1 to bind ICAP1, and that KRIT1 antagonizes ICAP1-modulated integrin activation using this site. We also find that KRIT1 contains an N-terminal Nudix domain, in a region previously designated as unstructured. We therefore provide insights to integrin regulation and CCM-associated KRIT1 function.

Mechanism for KRIT1 Release of ICAP1-Mediated Suppression of Integrin Activation.,Liu W, Draheim KM, Zhang R, Calderwood DA, Boggon TJ Mol Cell. 2013 Jan 9. pii: S1097-2765(12)01014-3. doi:, 10.1016/j.molcel.2012.12.005. PMID:23317506^[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
↑ Liu W, Draheim KM, Zhang R, Calderwood DA, Boggon TJ. Mechanism for KRIT1 Release of ICAP1-Mediated Suppression of Integrin Activation. Mol Cell. 2013 Jan 9. pii: S1097-2765(12)01014-3. doi:, 10.1016/j.molcel.2012.12.005. PMID:23317506 doi:http://dx.doi.org/10.1016/j.molcel.2012.12.005

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4dx8"

@@ Line 1: / Line 1: @@
 ==ICAP1 in complex with KRIT1 N-terminus==
-<StructureSection load='4dx8' size='340' side='right' caption='[[4dx8]], [[Resolution|resolution]] 2.54&Aring;' scene=''>
+<StructureSection load='4dx8' size='340' side='right'caption='[[4dx8]], [[Resolution|resolution]] 2.54&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4dx8]] is a 8 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=4DX8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DX8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4dx8]] is a 8 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=4DX8 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=4DX8 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4dx9|4dx9]], [[4dxa|4dxa]]</td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ICAP1, Integrin cytoplasmic domain-associated protein 1 (ICAP1), ITGB1BP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CCM1, Krev interaction trapped protein 1 (KRIT1), KRIT1 ([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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4dx8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dx8 OCA], [http://pdbe.org/4dx8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dx8 RCSB], [http://www.ebi.ac.uk/pdbsum/4dx8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dx8 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=4dx8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dx8 OCA], [http://pdbe.org/4dx8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dx8 RCSB], [http://www.ebi.ac.uk/pdbsum/4dx8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dx8 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 27: / Line 27: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Boggon, T J]]
 [[Category: Calderwood, D A]]
@@ Line 36: / Line 37: @@
 [[Category: Nudix fold]]
 [[Category: Protein binding]]
+[[Category: Protein-protein complex]]
 [[Category: Protein-protein interaction]]
-[[Category: Protein-protien complex]]
 [[Category: Ptb domain]]

4dx8

From Proteopedia

Revision as of 06:58, 2 September 2020

ICAP1 in complex with KRIT1 N-terminus

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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