|
|
| (4 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| - | {{STRUCTURE_4g1m| PDB=4g1m | SCENE= }} | |
| - | ===Re-refinement of alpha V beta 3 structure=== | |
| - | {{ABSTRACT_PUBMED_19704023}} | |
| | | | |
| - | ==Disease== | + | ==Re-refinement of alpha V beta 3 structure== |
| - | [[http://www.uniprot.org/uniprot/ITB3_HUMAN ITB3_HUMAN]] Defects in ITGB3 are a cause of Glanzmann thrombasthenia (GT) [MIM:[http://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:2392682</ref><ref>PMID:1371279</ref><ref>PMID:1602006</ref><ref>PMID:1438206</ref><ref>PMID:8781422</ref><ref>PMID:9376589</ref><ref>PMID:9215749</ref><ref>PMID:9790984</ref><ref>PMID:9684783</ref><ref>PMID:10233432</ref><ref>PMID:11588040</ref><ref>PMID:11897046</ref><ref>PMID:12083483</ref><ref>PMID:12353082</ref><ref>PMID:15583747</ref><ref>PMID:15634267</ref><ref>PMID:15748237</ref> | + | <StructureSection load='4g1m' size='340' side='right'caption='[[4g1m]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[4g1m]] 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=4G1M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4G1M FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=4g1m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g1m OCA], [https://pdbe.org/4g1m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4g1m RCSB], [https://www.ebi.ac.uk/pdbsum/4g1m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4g1m ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/ITAV_HUMAN ITAV_HUMAN] The alpha-V integrins are receptors for vitronectin, cytotactin, fibronectin, fibrinogen, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin and vWF. They recognize the sequence R-G-D in a wide array of ligands. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions. |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Many questions about the significance of structural features of integrin alpha(V)beta(3) with respect to its mechanism of activation remain. We have determined and re-refined crystal structures of the alpha(V)beta(3) ectodomain linked to C-terminal coiled coils (alpha(V)beta(3)-AB) and four transmembrane (TM) residues in each subunit (alpha(V)beta(3)-1TM), respectively. The alpha(V) and beta(3) subunits with four and eight extracellular domains, respectively, are bent at knees between the integrin headpiece and lower legs, and the headpiece has the closed, low-affinity conformation. The structures differ in the occupancy of three metal-binding sites in the betaI domain. Occupancy appears to be related to the pH of crystallization, rather than to the physiologic regulation of ligand binding at the central, metal ion-dependent adhesion site. No electron density was observed for TM residues and much of the alpha(V) linker. alpha(V)beta(3)-AB and alpha(V)beta(3)-1TM demonstrate flexibility in the linker between their extracellular and TM domains, rather than the previously proposed rigid linkage. A previously postulated interface between the alpha(V) and beta(3) subunits at their knees was also not supported, because it lacks high-quality density, required rebuilding in alpha(V)beta(3)-1TM, and differed markedly between alpha(V)beta(3)-1TM and alpha(V)beta(3)-AB. Together with the variation in domain-domain orientation within their bent ectodomains between alpha(V)beta(3)-AB and alpha(V)beta(3)-1TM, these findings are compatible with the requirement for large structural changes, such as extension at the knees and headpiece opening, in conveying activation signals between the extracellular ligand-binding site and the cytoplasm. |
| | | | |
| - | ==Function==
| + | alpha(V)beta(3) Integrin Crystal Structures and Their Functional Implications.,Dong X, Mi LZ, Zhu J, Wang W, Hu P, Luo BH, Springer TA Biochemistry. 2012 Nov 6;51(44):8814-28. doi: 10.1021/bi300734n. Epub 2012 Oct, 29. PMID:23106217<ref>PMID:23106217</ref> |
| - | [[http://www.uniprot.org/uniprot/ITAV_HUMAN ITAV_HUMAN]] The alpha-V integrins are receptors for vitronectin, cytotactin, fibronectin, fibrinogen, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin and vWF. They recognize the sequence R-G-D in a wide array of ligands. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions. [[http://www.uniprot.org/uniprot/ITB3_HUMAN ITB3_HUMAN]] Integrin alpha-V/beta-3 is a receptor for cytotactin, fibronectin, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin, vitronectin and von Willebrand factor. Integrin alpha-IIb/beta-3 is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. Integrins alpha-IIb/beta-3 and alpha-V/beta-3 recognize the sequence R-G-D in a wide array of ligands. Integrin alpha-IIb/beta-3 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 surface. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.
| + | |
| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | [[4g1m]] is a 2 chain structure with sequence 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=4G1M OCA].
| + | </div> |
| | + | <div class="pdbe-citations 4g1m" style="background-color:#fffaf0;"></div> |
| | | | |
| - | ==Reference== | + | ==See Also== |
| - | <ref group="xtra">PMID:019704023</ref><references group="xtra"/><references/>
| + | *[[Integrin 3D structures|Integrin 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Mi, L.]] | + | [[Category: Large Structures]] |
| - | [[Category: Springer, T A.]] | + | [[Category: Mi L]] |
| - | [[Category: Zhu, J.]] | + | [[Category: Springer TA]] |
| - | [[Category: Protein binding]] | + | [[Category: Zhu J]] |
| Structural highlights
4g1m is a 2 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 |
Function
ITAV_HUMAN The alpha-V integrins are receptors for vitronectin, cytotactin, fibronectin, fibrinogen, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin and vWF. They recognize the sequence R-G-D in a wide array of ligands. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.
Publication Abstract from PubMed
Many questions about the significance of structural features of integrin alpha(V)beta(3) with respect to its mechanism of activation remain. We have determined and re-refined crystal structures of the alpha(V)beta(3) ectodomain linked to C-terminal coiled coils (alpha(V)beta(3)-AB) and four transmembrane (TM) residues in each subunit (alpha(V)beta(3)-1TM), respectively. The alpha(V) and beta(3) subunits with four and eight extracellular domains, respectively, are bent at knees between the integrin headpiece and lower legs, and the headpiece has the closed, low-affinity conformation. The structures differ in the occupancy of three metal-binding sites in the betaI domain. Occupancy appears to be related to the pH of crystallization, rather than to the physiologic regulation of ligand binding at the central, metal ion-dependent adhesion site. No electron density was observed for TM residues and much of the alpha(V) linker. alpha(V)beta(3)-AB and alpha(V)beta(3)-1TM demonstrate flexibility in the linker between their extracellular and TM domains, rather than the previously proposed rigid linkage. A previously postulated interface between the alpha(V) and beta(3) subunits at their knees was also not supported, because it lacks high-quality density, required rebuilding in alpha(V)beta(3)-1TM, and differed markedly between alpha(V)beta(3)-1TM and alpha(V)beta(3)-AB. Together with the variation in domain-domain orientation within their bent ectodomains between alpha(V)beta(3)-AB and alpha(V)beta(3)-1TM, these findings are compatible with the requirement for large structural changes, such as extension at the knees and headpiece opening, in conveying activation signals between the extracellular ligand-binding site and the cytoplasm.
alpha(V)beta(3) Integrin Crystal Structures and Their Functional Implications.,Dong X, Mi LZ, Zhu J, Wang W, Hu P, Luo BH, Springer TA Biochemistry. 2012 Nov 6;51(44):8814-28. doi: 10.1021/bi300734n. Epub 2012 Oct, 29. PMID:23106217[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Dong X, Mi LZ, Zhu J, Wang W, Hu P, Luo BH, Springer TA. alpha(V)beta(3) Integrin Crystal Structures and Their Functional Implications. Biochemistry. 2012 Nov 6;51(44):8814-28. doi: 10.1021/bi300734n. Epub 2012 Oct, 29. PMID:23106217 doi:http://dx.doi.org/10.1021/bi300734n
|
