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3fcu

From Proteopedia

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Structure of headpiece of integrin aIIBb3 in open conformation

Structural highlights

3fcu is a 6 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 2.9Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ITA2B_HUMAN Defects in ITGA2B are a cause of Glanzmann thrombasthenia (GT) [MIM:273800; also known as thrombasthenia of Glanzmann and Naegeli. GT is the most common inherited disease of platelets. It is an autosomal recessive disorder characterized by mucocutaneous bleeding of mild-to-moderate severity and the inability of this integrin to recognize macromolecular or synthetic peptide ligands. GT has been classified clinically into types I and II. In type I, platelets show absence of the glycoprotein IIb/beta-3 complexes at their surface and lack fibrinogen and clot retraction capability. In type II, the platelets express the glycoprotein IIb/beta-3 complex at reduced levels (5-20% controls), have detectable amounts of fibrinogen, and have low or moderate clot retraction capability. The platelets of GT 'variants' have normal or near normal (60-100%) expression of dysfunctional receptors.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13] ^[14] ^[15] ^[16] ^[17] ^[18] ^[19]

Function

ITA2B_HUMAN Integrin alpha-IIb/beta-3 is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. It recognizes the sequence R-G-D in a wide array of ligands. It recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in fibrinogen gamma chain. Following activation integrin alpha-IIb/beta-3 brings about platelet/platelet interaction through binding of soluble fibrinogen. This step leads to rapid platelet aggregation which physically plugs ruptured endothelial cell surface.

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

The complete ectodomain of integrin alpha(IIb)beta(3) reveals a bent, closed, low-affinity conformation, the beta knee, and a mechanism for linking cytoskeleton attachment to high affinity for ligand. Ca and Mg ions in the recognition site, including the synergistic metal ion binding site (SyMBS), are loaded prior to ligand binding. Electrophilicity of the ligand-binding Mg ion is increased in the open conformation. The beta(3) knee passes between the beta(3)-PSI and alpha(IIb)-knob to bury the lower beta leg in a cleft, from which it is released for extension. Different integrin molecules in crystals and EM reveal breathing that appears on pathway to extension. Tensile force applied to the extended ligand-receptor complex stabilizes the closed, low-affinity conformation. By contrast, an additional lateral force applied to the beta subunit to mimic attachment to moving actin filaments stabilizes the open, high-affinity conformation. This mechanism propagates allostery over long distances and couples cytoskeleton attachment of integrins to their high-affinity state.

Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces.,Zhu J, Luo BH, Xiao T, Zhang C, Nishida N, Springer TA Mol Cell. 2008 Dec 26;32(6):849-61. PMID:19111664^[20]

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

References

↑ Poncz M, Rifat S, Coller BS, Newman PJ, Shattil SJ, Parrella T, Fortina P, Bennett JS. Glanzmann thrombasthenia secondary to a Gly273-->Asp mutation adjacent to the first calcium-binding domain of platelet glycoprotein IIb. J Clin Invest. 1994 Jan;93(1):172-9. PMID:8282784 doi:http://dx.doi.org/10.1172/JCI116942
↑ Wilcox DA, Wautier JL, Pidard D, Newman PJ. A single amino acid substitution flanking the fourth calcium binding domain of alpha IIb prevents maturation of the alpha IIb beta 3 integrin complex. J Biol Chem. 1994 Feb 11;269(6):4450-7. PMID:7508443
↑ Wilcox DA, Paddock CM, Lyman S, Gill JC, Newman PJ. Glanzmann thrombasthenia resulting from a single amino acid substitution between the second and third calcium-binding domains of GPIIb. Role of the GPIIb amino terminus in integrin subunit association. J Clin Invest. 1995 Apr;95(4):1553-60. PMID:7706461 doi:http://dx.doi.org/10.1172/JCI117828
↑ Basani RB, Vilaire G, Shattil SJ, Kolodziej MA, Bennett JS, Poncz M. Glanzmann thrombasthenia due to a two amino acid deletion in the fourth calcium-binding domain of alpha IIb: demonstration of the importance of calcium-binding domains in the conformation of alpha IIb beta 3. Blood. 1996 Jul 1;88(1):167-73. PMID:8704171
↑ French DL, Coller BS. Hematologically important mutations: Glanzmann thrombasthenia. Blood Cells Mol Dis. 1997;23(1):39-51. PMID:9215749 doi:10.1006/bcmd.1997.0117
↑ Grimaldi CM, Chen F, Wu C, Weiss HJ, Coller BS, French DL. Glycoprotein IIb Leu214Pro mutation produces glanzmann thrombasthenia with both quantitative and qualitative abnormalities in GPIIb/IIIa. Blood. 1998 Mar 1;91(5):1562-71. PMID:9473221
↑ Tadokoro S, Tomiyama Y, Honda S, Arai M, Yamamoto N, Shiraga M, Kosugi S, Kanakura Y, Kurata Y, Matsuzawa Y. A Gln747-->Pro substitution in the IIb subunit is responsible for a moderate IIbbeta3 deficiency in Glanzmann thrombasthenia. Blood. 1998 Oct 15;92(8):2750-8. PMID:9763559
↑ Ambo H, Kamata T, Handa M, Kawai Y, Oda A, Murata M, Takada Y, Ikeda Y. Novel point mutations in the alphaIIb subunit (Phe289-->Ser, Glu324-->Lys and Gln747-->Pro) causing thrombasthenic phenotypes in four Japanese patients. Br J Haematol. 1998 Aug;102(3):829-40. PMID:9722314
↑ Ruan J, Peyruchaud O, Alberio L, Valles G, Clemetson K, Bourre F, Nurden AT. Double heterozygosity of the GPIIb gene in a Swiss patient with Glanzmann's thrombasthenia. Br J Haematol. 1998 Sep;102(4):918-25. PMID:9734640
↑ Gonzalez-Manchon C, Fernandez-Pinel M, Arias-Salgado EG, Ferrer M, Alvarez MV, Garcia-Munoz S, Ayuso MS, Parrilla R. Molecular genetic analysis of a compound heterozygote for the glycoprotein (GP) IIb gene associated with Glanzmann's thrombasthenia: disruption of the 674-687 disulfide bridge in GPIIb prevents surface exposure of GPIIb-IIIa complexes. Blood. 1999 Feb 1;93(3):866-75. PMID:9920835
↑ Basani RB, French DL, Vilaire G, Brown DL, Chen F, Coller BS, Derrick JM, Gartner TK, Bennett JS, Poncz M. A naturally occurring mutation near the amino terminus of alphaIIb defines a new region involved in ligand binding to alphaIIbbeta3. Blood. 2000 Jan 1;95(1):180-8. PMID:10607701
↑ Vinciguerra C, Bordet JC, Beaune G, Grenier C, Dechavanne M, Negrier C. Description of 10 new mutations in platelet glycoprotein IIb (alphaIIb) and glycoprotein IIIa (beta3) genes. Platelets. 2001 Dec;12(8):486-95. PMID:11798398 doi:10.1080/095371001317126383
↑ Tanaka S, Hayashi T, Hori Y, Terada C, Han KS, Ahn HS, Bourre F, Tani Y. A Leu55 to Pro substitution in the integrin alphaIIb is responsible for a case of Glanzmann's thrombasthenia. Br J Haematol. 2002 Sep;118(3):833-5. PMID:12181054
↑ D'Andrea G, Colaizzo D, Vecchione G, Grandone E, Di Minno G, Margaglione M. Glanzmann's thrombasthenia: identification of 19 new mutations in 30 patients. Thromb Haemost. 2002 Jun;87(6):1034-42. PMID:12083483
↑ Mitchell WB, Li JH, Singh F, Michelson AD, Bussel J, Coller BS, French DL. Two novel mutations in the alpha IIb calcium-binding domains identify hydrophobic regions essential for alpha IIbbeta 3 biogenesis. Blood. 2003 Mar 15;101(6):2268-76. Epub 2002 Nov 7. PMID:12424194 doi:10.1182/blood-2002-07-2266
↑ Kiyoi T, Tomiyama Y, Honda S, Tadokoro S, Arai M, Kashiwagi H, Kosugi S, Kato H, Kurata Y, Matsuzawa Y. A naturally occurring Tyr143His alpha IIb mutation abolishes alpha IIb beta 3 function for soluble ligands but retains its ability for mediating cell adhesion and clot retraction: comparison with other mutations causing ligand-binding defects. Blood. 2003 May 1;101(9):3485-91. Epub 2002 Dec 27. PMID:12506038 doi:10.1182/blood-2002-07-2144
↑ Nurden AT, Breillat C, Jacquelin B, Combrie R, Freedman J, Blanchette VS, Schmugge M, Rand ML. Triple heterozygosity in the integrin alphaIIb subunit in a patient with Glanzmann's thrombasthenia. J Thromb Haemost. 2004 May;2(5):813-9. PMID:15099289 doi:10.1046/j.1538-7836.2004.00711.x
↑ Rosenberg N, Landau M, Luboshitz J, Rechavi G, Seligsohn U. A novel Phe171Cys mutation in integrin alpha causes Glanzmann thrombasthenia by abrogating alphabeta complex formation. J Thromb Haemost. 2004 Jul;2(7):1167-75. PMID:15219201 doi:10.1111/j.1538-7836.2004.00758.x
↑ Jayo A, Pabon D, Lastres P, Jimenez-Yuste V, Gonzalez-Manchon C. Type II Glanzmann thrombasthenia in a compound heterozygote for the alpha IIb gene. A novel missense mutation in exon 27. Haematologica. 2006 Oct;91(10):1352-9. PMID:17018384
↑ Zhu J, Luo BH, Xiao T, Zhang C, Nishida N, Springer TA. Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Mol Cell. 2008 Dec 26;32(6):849-61. PMID:19111664 doi:10.1016/j.molcel.2008.11.018

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3fcu"

@@ Line 1: / Line 1: @@
-{{Seed}}
-[[Image:3fcu.jpg|left|200px]]
-<!--
+==Structure of headpiece of integrin aIIBb3 in open conformation==
-The line below this paragraph, containing "STRUCTURE_3fcu", creates the "Structure Box" on the page.
+<StructureSection load='3fcu' size='340' side='right'caption='[[3fcu]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[3fcu]] is a 6 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=3FCU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FCU FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9&#8491;</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=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
-{{STRUCTURE_3fcu|  PDB=3fcu  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3fcu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fcu OCA], [https://pdbe.org/3fcu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3fcu RCSB], [https://www.ebi.ac.uk/pdbsum/3fcu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3fcu ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/ITA2B_HUMAN ITA2B_HUMAN] Defects in ITGA2B are a cause of Glanzmann thrombasthenia (GT) [MIM:[https://omim.org/entry/273800 273800]; also known as thrombasthenia of Glanzmann and Naegeli. GT is the most common inherited disease of platelets. It is an autosomal recessive disorder characterized by mucocutaneous bleeding of mild-to-moderate severity and the inability of this integrin to recognize macromolecular or synthetic peptide ligands. GT has been classified clinically into types I and II. In type I, platelets show absence of the glycoprotein IIb/beta-3 complexes at their surface and lack fibrinogen and clot retraction capability. In type II, the platelets express the glycoprotein IIb/beta-3 complex at reduced levels (5-20% controls), have detectable amounts of fibrinogen, and have low or moderate clot retraction capability. The platelets of GT 'variants' have normal or near normal (60-100%) expression of dysfunctional receptors.<ref>PMID:8282784</ref> <ref>PMID:7508443</ref> <ref>PMID:7706461</ref> <ref>PMID:8704171</ref> <ref>PMID:9215749</ref> <ref>PMID:9473221</ref> <ref>PMID:9763559</ref> <ref>PMID:9722314</ref> <ref>PMID:9734640</ref> <ref>PMID:9920835</ref> <ref>PMID:10607701</ref> <ref>PMID:11798398</ref> <ref>PMID:12181054</ref> <ref>PMID:12083483</ref> <ref>PMID:12424194</ref> <ref>PMID:12506038</ref> <ref>PMID:15099289</ref> <ref>PMID:15219201</ref> <ref>PMID:17018384</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/ITA2B_HUMAN ITA2B_HUMAN] Integrin alpha-IIb/beta-3 is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. It recognizes the sequence R-G-D in a wide array of ligands. It recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in fibrinogen gamma chain. Following activation integrin alpha-IIb/beta-3 brings about platelet/platelet interaction through binding of soluble fibrinogen. This step leads to rapid platelet aggregation which physically plugs ruptured endothelial cell surface.
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fc/3fcu_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</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=3fcu ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The complete ectodomain of integrin alpha(IIb)beta(3) reveals a bent, closed, low-affinity conformation, the beta knee, and a mechanism for linking cytoskeleton attachment to high affinity for ligand. Ca and Mg ions in the recognition site, including the synergistic metal ion binding site (SyMBS), are loaded prior to ligand binding. Electrophilicity of the ligand-binding Mg ion is increased in the open conformation. The beta(3) knee passes between the beta(3)-PSI and alpha(IIb)-knob to bury the lower beta leg in a cleft, from which it is released for extension. Different integrin molecules in crystals and EM reveal breathing that appears on pathway to extension. Tensile force applied to the extended ligand-receptor complex stabilizes the closed, low-affinity conformation. By contrast, an additional lateral force applied to the beta subunit to mimic attachment to moving actin filaments stabilizes the open, high-affinity conformation. This mechanism propagates allostery over long distances and couples cytoskeleton attachment of integrins to their high-affinity state.
-===Structure of headpiece of integrin aIIBb3 in open conformation===
+Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces.,Zhu J, Luo BH, Xiao T, Zhang C, Nishida N, Springer TA Mol Cell. 2008 Dec 26;32(6):849-61. PMID:19111664<ref>PMID:19111664</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 3fcu" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_19111664}}, adds the Publication Abstract to the page
+*[[Integrin 3D structures|Integrin 3D structures]]
-(as it appears on PubMed at http://www.pubmed.gov), where 19111664 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_19111664}}
+__TOC__
+</StructureSection>
-==Disease==
-Known disease associated with this structure: Glanzmann thrombasthenia, type A OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607759 607759]], Thrombocytopenia, neonatal alloimmune OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607759 607759]]
-==About this Structure==
-FCU is a 6 chains structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FCU OCA].
-==Reference==
-<ref group="xtra">PMID:19111664</ref><references group="xtra"/>
 [[Category: Homo sapiens]]
-[[Category: Luo, B H.]]
+[[Category: Large Structures]]
-[[Category: Nishida, N.]]
+[[Category: Luo B-H]]
-[[Category: Springer, T A.]]
+[[Category: Nishida N]]
-[[Category: Xiao, T.]]
+[[Category: Springer TA]]
-[[Category: Zhang, C.]]
+[[Category: Xiao T]]
-[[Category: Zhu, J.]]
+[[Category: Zhang C]]
-[[Category: Allostery]]
+[[Category: Zhu J]]
-[[Category: Alternative splicing]]
-[[Category: Cell adhesion]]
-[[Category: Cell adhesion/blood clotting complex]]
-[[Category: Cell adhesion/immune system complex]]
-[[Category: Crystal structure]]
-[[Category: Disease mutation]]
-[[Category: Fibrinogen binding]]
-[[Category: Glycoprotein]]
-[[Category: Host-virus interaction]]
-[[Category: Integrin]]
-[[Category: Membrane]]
-[[Category: Phosphoprotein]]
-[[Category: Platelet integrin alphaiibbeta3]]
-[[Category: Polymorphism]]
-[[Category: Receptor]]
-[[Category: Therapeutic antagonism]]
-[[Category: Transmembrane]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 21 10:49:26 2009''

3fcu

From Proteopedia

Current revision

Structure of headpiece of integrin aIIBb3 in open conformation

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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