3jtc

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{{STRUCTURE_3jtc| PDB=3jtc | SCENE= }}
 
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===Importance of Mg2+ in the Ca2+-Dependent Folding of the gamma-Carboxyglutamic Acid Domains of Vitamin K-Dependent clotting and anticlotting Proteins===
 
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{{ABSTRACT_PUBMED_23454357}}
 
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==Disease==
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==Importance of Mg2+ in the Ca2+-Dependent Folding of the gamma-Carboxyglutamic Acid Domains of Vitamin K-Dependent clotting and anticlotting Proteins==
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[[http://www.uniprot.org/uniprot/PROC_HUMAN PROC_HUMAN]] Defects in PROC are the cause of thrombophilia due to protein C deficiency, autosomal dominant (THPH3) [MIM:[http://omim.org/entry/176860 176860]]. A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. However, many adults with heterozygous disease may be asymptomatic. Individuals with decreased amounts of protein C are classically referred to as having type I protein C deficiency and those with normal amounts of a functionally defective protein as having type II deficiency.<ref>PMID:8560401</ref> <ref>PMID:2437584</ref> <ref>PMID:2602169</ref> <ref>PMID:1868249</ref> <ref>PMID:1347706</ref> <ref>PMID:1511989</ref> <ref>PMID:1301959</ref> <ref>PMID:8499568</ref> <ref>PMID:8292730</ref> <ref>PMID:8398832</ref> <ref>PMID:7865674</ref> <ref>PMID:7792728</ref> <ref>PMID:8829639</ref> <ref>PMID:9798967</ref> Defects in PROC are the cause of thrombophilia due to protein C deficiency, autosomal recessive (THPH4) [MIM:[http://omim.org/entry/612304 612304]]. A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. It results in a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia. The severe form leads to neonatal death through massive neonatal venous thrombosis. Often associated with ecchymotic skin lesions which can turn necrotic called purpura fulminans, this disorder is very rare.
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<StructureSection load='3jtc' size='340' side='right'caption='[[3jtc]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3jtc]] is a 4 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=3JTC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3JTC FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</td></tr>
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<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=CGU:GAMMA-CARBOXY-GLUTAMIC+ACID'>CGU</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PTY:PHOSPHATIDYLETHANOLAMINE'>PTY</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3jtc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jtc OCA], [https://pdbe.org/3jtc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3jtc RCSB], [https://www.ebi.ac.uk/pdbsum/3jtc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3jtc ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/EPCR_HUMAN EPCR_HUMAN] Binds activated protein C. Enhances protein C activation by the thrombin-thrombomodulin complex; plays a role in the protein C pathway controlling blood coagulation.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Crystal structures of factor (F) VIIa/soluble tissue factor (TF), obtained under high Mg2+ (50mM Mg2+/5mM Ca2+), have three of seven Ca2+ sites in the gamma-carboxyglutamic acid (Gla) domain replaced by Mg2+ at positions 1, 4, and 7. We now report structures under low Mg2+ (2.5mM Mg2+/5mM Ca2+) as well as under high Ca2+ (5mM Mg2+/45mM Ca2+). Under low Mg2+, four Ca2+ and three Mg2+ occupy the same positions as in high-Mg2+ structures. Conversely, under low Mg2+, reexamination of the structure of Gla domain of activated Protein C (APC) complexed with soluble endothelial Protein C receptor (sEPCR) has position 4 occupied by Ca2+ and positions 1 and 7 by Mg2+. Nonetheless, in direct binding experiments, Mg2+ replaced three Ca2+ sites in the unliganded Protein C or APC. Further, the high-Ca2+ condition was necessary to replace Mg4 in the FVIIa/soluble TF structure. In biological studies, Mg2+ enhanced phospholipid binding to FVIIa and APC at physiological Ca2+. Additionally, Mg2+ potentiated phospholipid-dependent activations of FIX and FX by FVIIa/TF and inactivation of activated factor V by APC. Since APC and FVIIa bind to sEPCR involving similar interactions, we conclude that under the low-Mg2+ condition, sEPCR binding to APC-Gla (or FVIIa-Gla) replaces Mg4 by Ca4 with an attendant conformational change in the Gla domain omega-loop. Moreover, since phospholipid and sEPCR bind to FVIIa or APC via the omega-loop, we predict that phospholipid binding also induces the functional Ca4 conformation in this loop. Cumulatively, the data illustrate that Mg2+ and Ca2+ act in concert to promote coagulation and anticoagulation.
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==Function==
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Structural and Functional Studies of gamma-Carboxyglutamic Acid Domains of Factor VIIa and Activated Protein C: Role of Magnesium at Physiological Calcium.,Vadivel K, Agah S, Messer AS, Cascio D, Bajaj MS, Krishnaswamy S, Esmon CT, Padmanabhan K, Bajaj SP J Mol Biol. 2013 Feb 20. pii: S0022-2836(13)00104-6. doi:, 10.1016/j.jmb.2013.02.017. PMID:23454357<ref>PMID:23454357</ref>
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[[http://www.uniprot.org/uniprot/EPCR_HUMAN EPCR_HUMAN]] Binds activated protein C. Enhances protein C activation by the thrombin-thrombomodulin complex; plays a role in the protein C pathway controlling blood coagulation. [[http://www.uniprot.org/uniprot/PROC_HUMAN PROC_HUMAN]] Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids.
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[3jtc]] is a 4 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=3JTC OCA].
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</div>
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<div class="pdbe-citations 3jtc" style="background-color:#fffaf0;"></div>
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==Reference==
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== References ==
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<ref group="xtra">PMID:023454357</ref><references group="xtra"/><references/>
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Agah, S.]]
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[[Category: Large Structures]]
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[[Category: Bajaj, S P.]]
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[[Category: Agah S]]
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[[Category: Cascio, D.]]
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[[Category: Bajaj SP]]
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[[Category: Esmon, C.]]
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[[Category: Cascio D]]
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[[Category: Krishnaswamy, S.]]
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[[Category: Esmon C]]
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[[Category: Padmanabhan, K.]]
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[[Category: Krishnaswamy S]]
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[[Category: Vadivel, K.]]
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[[Category: Padmanabhan K]]
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[[Category: Blood clotting]]
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[[Category: Vadivel K]]
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[[Category: Blood coagulation]]
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[[Category: Ca ion binding]]
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[[Category: Cleavage on pair of basic residue]]
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[[Category: Disease mutation]]
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[[Category: Disulfide bond]]
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[[Category: Egf-like domain]]
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[[Category: Gamma-carboxyglutamic acid]]
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[[Category: Glycoprotein]]
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[[Category: Hydrolase]]
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[[Category: Hydroxylation]]
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[[Category: Membrane]]
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[[Category: Phospholipid binding groove]]
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[[Category: Protease]]
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[[Category: Receptor]]
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[[Category: Serine protease]]
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[[Category: Thrombophilia]]
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[[Category: Transmembrane]]
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[[Category: Zymogen]]
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Current revision

Importance of Mg2+ in the Ca2+-Dependent Folding of the gamma-Carboxyglutamic Acid Domains of Vitamin K-Dependent clotting and anticlotting Proteins

PDB ID 3jtc

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