3jtc

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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

Structural highlights

3jtc is a 4 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 1.6Å
Ligands:CA, CGU, MG, NAG, PTY
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.

Publication Abstract from PubMed

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.

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[1]

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

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Citations
4 reviews cite this structure
Sobczak et al. (2019)
No citations found

References

  1. Vadivel K, Agah S, Messer AS, Cascio D, Bajaj MS, Krishnaswamy S, Esmon CT, Padmanabhan K, Bajaj SP. Structural and Functional Studies of gamma-Carboxyglutamic Acid Domains of Factor VIIa and Activated Protein C: Role of Magnesium at Physiological Calcium. J Mol Biol. 2013 Feb 20. pii: S0022-2836(13)00104-6. doi:, 10.1016/j.jmb.2013.02.017. PMID:23454357 doi:10.1016/j.jmb.2013.02.017

Contents


PDB ID 3jtc

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