Localization of the specific binding site for magnesium(II) ions in factor IX

Sekiya, Fujio; Yoshida, Misa; Yamashita, Toshiko; Morita, Takashi

doi:10.1016/0014-5793(96)00813-7

Cited by 18 publications

(9 citation statements)

References 27 publications

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“…It is also known that Mg 2ϩ ions increase the affinity between factor IXa and antibodies (11,13) and the biological activity of factor IXa in the presence of factor VIIIa (10). The interaction between factors IXa and VIIIa is well documented by experiments indicating that epidermal growth factor and the serine protease domains of factor IXa were involved in the interaction with factor VIIIa (30 -35).…”

Section: Discussionmentioning

confidence: 99%

“…Gla domain peptide (residues 1-46, IXGD1-46) was prepared as described (13). IX-bp was purified from the venom of T. flavoviridis as previously reported (22).…”

Section: Methodsmentioning

confidence: 99%

“…In addition to the acceleration in activity by Mg 2ϩ ions, folding of the native tertiary structure of factor IX Gla domain appears to require not only Ca 2ϩ but Mg 2ϩ ions (11,13). Snake venom obtained from Trimeresurus flavoviridis contains a protein that can bind to either factor IX or factor X and is called a factor IX/factor X-binding protein (IX/X-bp) (14,15).…”

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confidence: 99%

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Crystal Structure of Mg2+- and Ca2+-bound Gla Domain of Factor IX Complexed with Binding Protein

Shikamoto

Morita

Fujimoto

et al. 2003

Journal of Biological Chemistry

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104

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Section: Discussionmentioning

confidence: 99%

“…Gla domain peptide (residues 1-46, IXGD1-46) was prepared as described (13). IX-bp was purified from the venom of T. flavoviridis as previously reported (22).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Crystal Structure of Mg2+- and Ca2+-bound Gla Domain of Factor IX Complexed with Binding Protein

Shikamoto

Morita

Fujimoto

et al. 2003

Journal of Biological Chemistry

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104

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“…Our K d values for interaction of phospholipid at saturating concentrations of Ca 2+ for FVIIa and APC agree well with the previous reports. 49,50 Earlier, Mg 2+ has been shown to accelerate synthetic phospholipid-dependent coagulation reactions involving FVII, 12 FIX, 13,15,16,51 FX 20 and prothrombin. 9 Here, we show that Mg 2+ similarly accelerates Ca 2+ -dependent activations of FX and FIX by FVIIa/TF assembled on biological membranes (Fig.…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Studies of γ-Carboxyglutamic Acid Domains of Factor VIIa and Activated Protein C: Role of Magnesium at Physiological Calcium

Vadivel

Agah

Messer

et al. 2013

Journal of Molecular Biology

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Crystal structures of factor (F) VIIa/soluble (s) tissue factor (TF), obtained under high Mg2+ (50 mM Mg2+/5 mM Ca2+), have three of seven Ca2+-sites in the γ-Carboxyglutamic Acid (Gla) domain replaced by Mg2+ at positions 1, 4 and 7. We now report structures under low Mg2+ (2.5 mM Mg2+/5 mM Ca2+) as well as under high Ca2+ (5 mM Mg2+/45 mM 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 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/sTF 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 FVa 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 ω-loop. Moreover, since phospholipid and sEPCR bind to FVIIa or APC via the ω-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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“…Recently, it has been reported that Mg 2ϩ plays an important role in physiologic coagulation (23)(24)(25)(26). However, Mg 2ϩ sites in FVIIa have not been identified.…”

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confidence: 99%

High Resolution Structures of p-Aminobenzamidine- and Benzamidine-VIIa/Soluble Tissue Factor

Bajaj

Schmidt

Agah

et al. 2006

Journal of Biological Chemistry

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Factor VIIa (FVIIa) consists of a gamma-carboxyglutamic acid (Gla) domain, two epidermal growth factor-like domains, and a protease domain. FVIIa binds seven Ca(2+) ions in the Gla, one in the EGF1, and one in the protease domain. However, blood contains both Ca(2+) and Mg(2+), and the Ca(2+) sites in FVIIa that could be specifically occupied by Mg(2+) are unknown. Furthermore, FVIIa contains a Na(+) and two Zn(2+) sites, but ligands for these cations are undefined. We obtained p-aminobenzamidine-VIIa/soluble tissue factor (sTF) crystals under conditions containing Ca(2+), Mg(2+), Na(+), and Zn(2+). The crystal diffracted to 1.8A resolution, and the final structure has an R-factor of 19.8%. In this structure, the Gla domain has four Ca(2+) and three bound Mg(2+). The EGF1 domain contains one Ca(2+) site, and the protease domain contains one Ca(2+), one Na(+), and two Zn(2+) sites. (45)Ca(2+) binding in the presence/absence of Mg(2+) to FVIIa, Gla-domainless FVIIa, and prothrombin fragment 1 supports the crystal data. Furthermore, unlike in other serine proteases, the amide N of Gly(193) in FVIIa points away from the oxyanion hole in this structure. Importantly, the oxyanion hole is also absent in the benzamidine-FVIIa/sTF structure at 1.87A resolution. However, soaking benzamidine-FVIIa/sTF crystals with d-Phe-Pro-Arg-chloromethyl ketone results in benzamidine displacement, d-Phe-Pro-Arg incorporation, and oxyanion hole formation by a flip of the 192-193 peptide bond in FVIIa. Thus, it is the substrate and not the TF binding that induces oxyanion hole formation and functional active site geometry in FVIIa. Absence of oxyanion hole is unusual and has biologic implications for FVIIa macromolecular substrate specificity and catalysis.

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Localization of the specific binding site for magnesium(II) ions in factor IX

Cited by 18 publications

References 27 publications

Crystal Structure of Mg2+- and Ca2+-bound Gla Domain of Factor IX Complexed with Binding Protein

Crystal Structure of Mg2+- and Ca2+-bound Gla Domain of Factor IX Complexed with Binding Protein

Structural and Functional Studies of γ-Carboxyglutamic Acid Domains of Factor VIIa and Activated Protein C: Role of Magnesium at Physiological Calcium

High Resolution Structures of p-Aminobenzamidine- and Benzamidine-VIIa/Soluble Tissue Factor

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