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• W2000549605 abstract "Human factor X is a two-chain, 58-kDa, vitamin K-dependent blood coagulation zymogen. The light chain of factor X consists of an NH2-terminal γ-carboxyglutamic acid (Gla) domain, followed by a few helical hydrophobic residues and the two epidermal growth factor-like domains, whereas the heavy chain contains the serine protease domain. In this study, native factor X was found to contain three classes of Ca2+-binding sites: two high affinity (Kd 100 ± 30 μm), four intermediate affinity (Kd 450 ± 70 μm), and five to six low affinity (Kd2 ± 0.2 mm). Decarboxylated factor X in which the Gla residues were converted to Glu retained the two high affinity sites (Kd 140 ± 20 μm). In contrast, factor X lacking the Gla domain as well as a part of the helical hydrophobic residues (des-44-X) retained only one high affinity Ca2+-binding site (Kd 130 ± 20 μm). Moreover, a synthetic peptide composed of residues 238–277 (58–97 in chymotrypsinogen numbering) from the protease domain of factor X bound one Ca2+ with high affinity (Kd 150 ± 20 μm). From competitive inhibition assays for binding of active site-blocked factor Xa to factor Va in the prothrombinase complex, theKd for peptide-Va interaction was calculated to be ∼10 μm as compared with 30 pm for factor Xa and ∼1.5 μm for decarboxylated factor Xa. A peptide containing residues 238–262(58–82) bound Ca2+ with reduced affinity (Kd ∼600 μm) and did not inhibit Xa:Va interaction. In contrast, a peptide containing residues 253–277(73–97) inhibited Xa:Va interaction (Kd ∼10 μm) but did not bind Ca2+. In additional studies, Ca2+ increased the amidolytic activity of native and des-44-Xa toward a tetrapeptide substrate (benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide) by approximately 1.6-fold. The half-maximal increase was observed at ∼150 μm Ca2+ and the effect was primarily on the kcat. Ca2+ also significantly protected cleavage at Arg-332-Gln-333(150–151) in the protease domain autolysis loop. Des-44-Xa in which the autolysis loop was cleaved possessed ≤5% of the amidolytic activity of the noncleaved form; however, the S1 binding site was not affected, as determined by the p-aminobenzamidine binding. Additionally, autolysis loop-cleaved, active site-blocked native factor Xa was calculated to have ∼10-fold reduced affinity for factor Va as compared with that of the noncleaved form. Human factor X is a two-chain, 58-kDa, vitamin K-dependent blood coagulation zymogen. The light chain of factor X consists of an NH2-terminal γ-carboxyglutamic acid (Gla) domain, followed by a few helical hydrophobic residues and the two epidermal growth factor-like domains, whereas the heavy chain contains the serine protease domain. In this study, native factor X was found to contain three classes of Ca2+-binding sites: two high affinity (Kd 100 ± 30 μm), four intermediate affinity (Kd 450 ± 70 μm), and five to six low affinity (Kd2 ± 0.2 mm). Decarboxylated factor X in which the Gla residues were converted to Glu retained the two high affinity sites (Kd 140 ± 20 μm). In contrast, factor X lacking the Gla domain as well as a part of the helical hydrophobic residues (des-44-X) retained only one high affinity Ca2+-binding site (Kd 130 ± 20 μm). Moreover, a synthetic peptide composed of residues 238–277 (58–97 in chymotrypsinogen numbering) from the protease domain of factor X bound one Ca2+ with high affinity (Kd 150 ± 20 μm). From competitive inhibition assays for binding of active site-blocked factor Xa to factor Va in the prothrombinase complex, theKd for peptide-Va interaction was calculated to be ∼10 μm as compared with 30 pm for factor Xa and ∼1.5 μm for decarboxylated factor Xa. A peptide containing residues 238–262(58–82) bound Ca2+ with reduced affinity (Kd ∼600 μm) and did not inhibit Xa:Va interaction. In contrast, a peptide containing residues 253–277(73–97) inhibited Xa:Va interaction (Kd ∼10 μm) but did not bind Ca2+. In additional studies, Ca2+ increased the amidolytic activity of native and des-44-Xa toward a tetrapeptide substrate (benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide) by approximately 1.6-fold. The half-maximal increase was observed at ∼150 μm Ca2+ and the effect was primarily on the kcat. Ca2+ also significantly protected cleavage at Arg-332-Gln-333(150–151) in the protease domain autolysis loop. Des-44-Xa in which the autolysis loop was cleaved possessed ≤5% of the amidolytic activity of the noncleaved form; however, the S1 binding site was not affected, as determined by the p-aminobenzamidine binding. Additionally, autolysis loop-cleaved, active site-blocked native factor Xa was calculated to have ∼10-fold reduced affinity for factor Va as compared with that of the noncleaved form. Factor X is a vitamin K-dependent multidomain protein that participates in the middle phase of blood coagulation (1Davie E.W. Fujikawa K. Kisiel W. Biochemistry. 1991; 29: 10363-10370Crossref Scopus (1616) Google Scholar). Factor X is essential for hemostasis since a reduction in its functional activity results in a rare autosomal recessive bleeding disorder known as Stuart-Prower factor deficiency (2Graham J.B. Barrow E.M. Hougie C. J. Clin. Invest. 1957; 36: 497-503Crossref PubMed Scopus (47) Google Scholar). The human protein is synthesized in the liver as a precursor molecule of 488 amino acids (3Leytus S.P. Foster D.C. Kurachi K. Davie E.W. Biochemistry. 1986; 25: 5098-5102Crossref PubMed Scopus (182) Google Scholar). The amino-terminal 40 amino acids constitute the prepro leader sequence, which is removed prior to secretion of the molecule. Additionally, during biosynthesis, the protein undergoes several posttranslational modifications including glycosylation, γ-carboxylation (of the first 11 glutamic acid residues), β-hydroxylation (of Asp-63), and removal of a tripeptide (Arg-Lys-Arg) between Arg-139 and Ser-143 (3Leytus S.P. Foster D.C. Kurachi K. Davie E.W. Biochemistry. 1986; 25: 5098-5102Crossref PubMed Scopus (182) Google Scholar). The resulting mature protein is a zymogen of serine protease factor Xa and consists of a light chain (amino acids 1–139) and a heavy chain (amino acids 143–448) held together by a single disulfide bond between Cys-132 and Cys-302.Gene arrangement, amino acid sequence, and modular structure of factor X strongly suggest that the protein is organized into several distinct domains (3Leytus S.P. Foster D.C. Kurachi K. Davie E.W. Biochemistry. 1986; 25: 5098-5102Crossref PubMed Scopus (182) Google Scholar, 4Padmanabhan K. Padmanabhan K.P. Tulinsky A. Park C.H. Bode W. Huber R. Blankenship D.T. Cardin A.D. Kisiel W. J. Mol. Biol. 1993; 232: 947-966Crossref PubMed Scopus (401) Google Scholar). The amino terminus of the light chain contains 11 γ-carboxyglutamic acid (Gla) 1The abbreviations and trivial names used are: Gla, γ-carboxyglutamic acid; DEGR-CK, dansyl-Glu-Gly-Arg-chloromethyl ketone; EGF, epidermal growth factor; des-44-X or -Xa, Gla-domainless human factor X or Xa; PC, phosphatidylcholine; PS, phosphatidylserine; BSA, bovine serum albumin; PL, phospholipid; p-AB,p-aminobenzamidine; peptide 1, peptide containing the sequence of 238–277(59–97) residues of factor X; peptide 2, peptide containing the sequence of 238–262(58–82) of factor X; peptide 3, peptide containing the sequence of 253–277(73–97) of factor X; S-2222, benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide; S-2238, H-d-Phe-Pip-Arg-p-nitroanilide; DEGR-Xa, factor Xa inactivated with DEGR-CK; DEGR-des-44-Xa, des-44-Xa inactivated with DEGR-CK; TBS, Tris-buffered saline; IIa, α-thrombin; dansyl, 5-dimethylaminonaphthalene-1-sulfonyl.1The abbreviations and trivial names used are: Gla, γ-carboxyglutamic acid; DEGR-CK, dansyl-Glu-Gly-Arg-chloromethyl ketone; EGF, epidermal growth factor; des-44-X or -Xa, Gla-domainless human factor X or Xa; PC, phosphatidylcholine; PS, phosphatidylserine; BSA, bovine serum albumin; PL, phospholipid; p-AB,p-aminobenzamidine; peptide 1, peptide containing the sequence of 238–277(59–97) residues of factor X; peptide 2, peptide containing the sequence of 238–262(58–82) of factor X; peptide 3, peptide containing the sequence of 253–277(73–97) of factor X; S-2222, benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide; S-2238, H-d-Phe-Pip-Arg-p-nitroanilide; DEGR-Xa, factor Xa inactivated with DEGR-CK; DEGR-des-44-Xa, des-44-Xa inactivated with DEGR-CK; TBS, Tris-buffered saline; IIa, α-thrombin; dansyl, 5-dimethylaminonaphthalene-1-sulfonyl. residues and represents the Gla domain (residues 1–39) of factor X (3Leytus S.P. Foster D.C. Kurachi K. Davie E.W. Biochemistry. 1986; 25: 5098-5102Crossref PubMed Scopus (182) Google Scholar). The Gla domain is followed by a short hydrophobic stack (residues 40–45) and two epidermal growth factor (EGF)-like domains (residues 46–84 (EGF1) and residues 85–128 (EGF2)). The amino terminus of the heavy chain of factor X contains the activation peptide region of 52 amino acids (residues 143–194) followed by the serine protease domain of 254 amino acids (residues 195–448), which features the active site triad of His-236(57), 2For comparison, factor X amino acid numbering system has been used. The number in parentheses refers to the chymotrypsin equivalents for the protease domain of factor Xa.2For comparison, factor X amino acid numbering system has been used. The number in parentheses refers to the chymotrypsin equivalents for the protease domain of factor Xa. Asp-282(102), and Ser-379(195) (3Leytus S.P. Foster D.C. Kurachi K. Davie E.W. Biochemistry. 1986; 25: 5098-5102Crossref PubMed Scopus (182) Google Scholar).During physiologic hemostasis, factor X can be activated by factor IXa, requiring Ca2+, phospholipid (PL), and factor VIIIa or factor VIIa requiring Ca2+ and tissue factor (1Davie E.W. Fujikawa K. Kisiel W. Biochemistry. 1991; 29: 10363-10370Crossref Scopus (1616) Google Scholar, 5Bajaj M.S. Ameri A. Bajaj S.P. Green D. Anticoagulants: Physiologic, Pathologic, and Pharmacologic. CRC Press, Boca Raton, FL1994: 41-65Google Scholar). A potent nonphysiologic activator of factor X is the coagulant protein from Russell's viper venom (6Di Scipio R.G. Hermodson M.A. Davie E.W. Biochemistry. 1977; 16: 5253-5260Crossref PubMed Scopus (115) Google Scholar). In all cases, the activation results from the cleavage of the Arg-194–Ile-195(15–16) bond in the heavy chain of factor X and release of a 52-residue activation peptide; the light chain remains unaltered during this process (3Leytus S.P. Foster D.C. Kurachi K. Davie E.W. Biochemistry. 1986; 25: 5098-5102Crossref PubMed Scopus (182) Google Scholar, 7Leytus S.P. Chung D.W. Kisiel W. Kurachi K. Davie E.W. Proc. Natl. Acad. Sci. U. S. A. 1984; 81: 3699-3702Crossref PubMed Scopus (98) Google Scholar). Factors X and Xaα 3The nomenclature used for factor Xa is that of Di Scipio et al. (6Di Scipio R.G. Hermodson M.A. Davie E.W. Biochemistry. 1977; 16: 5253-5260Crossref PubMed Scopus (115) Google Scholar). Factor Xaα is factor Xa consisting of a light chain (L, amino acids 1–139) and a heavy chain (Hα, amino acids 195–448). Factor Xaβ is factor Xaα lacking the ∼4 kDa fragment from the COOH terminus of the Hα chain. Factor Xaγ is factor Xaβ in which proteolysis has occurred in the autolysis loop in the Hβ chain. Factor Xaβγ is a mixture of factors Xaβ and Xaγ.3The nomenclature used for factor Xa is that of Di Scipio et al. (6Di Scipio R.G. Hermodson M.A. Davie E.W. Biochemistry. 1977; 16: 5253-5260Crossref PubMed Scopus (115) Google Scholar). Factor Xaα is factor Xa consisting of a light chain (L, amino acids 1–139) and a heavy chain (Hα, amino acids 195–448). Factor Xaβ is factor Xaα lacking the ∼4 kDa fragment from the COOH terminus of the Hα chain. Factor Xaγ is factor Xaβ in which proteolysis has occurred in the autolysis loop in the Hβ chain. Factor Xaβγ is a mixture of factors Xaβ and Xaγ. can also be converted to their respective β-forms where ∼4 kDa peptide is cleaved off from the COOH terminus of the heavy chain; this, however, does not result in a loss of coagulant activity (6Di Scipio R.G. Hermodson M.A. Davie E.W. Biochemistry. 1977; 16: 5253-5260Crossref PubMed Scopus (115) Google Scholar). Factor Xa converts prothrombin to thrombin in the coagulation cascade; for a physiologically significant rate, this reaction requires Ca2+, PL, and factor Va (8Mann K.G. Nesheim M.E. Church W.R. Haley P. Krishnaswamy S. Blood. 1990; 76: 1-16Crossref PubMed Google Scholar). Thus, Ca2+ plays an important role both in the activation of factor X and in the conversion of prothrombin to thrombin by factor Xa.Ca2+ binding to human factor X has been studied by Monroeet al. (9Monroe D.M. Deerfield D.W., II Olson D.L. Stewart T.N. Treanor R.E. Roberts H.R. Hiskey R.G. Pedersen L.G. Blood Coagul. Fibrinolysis. 1990; 1: 633-640PubMed Google Scholar). The authors reported that the protein contains one high affinity Gla-independent and 19 weak Gla-dependent Ca2+-binding sites (9Monroe D.M. Deerfield D.W., II Olson D.L. Stewart T.N. Treanor R.E. Roberts H.R. Hiskey R.G. Pedersen L.G. Blood Coagul. Fibrinolysis. 1990; 1: 633-640PubMed Google Scholar). In the present report, we have extensively investigated the Ca2+-binding properties of native, decarboxylated, and Gla domainless (des-44-X) human factor X. The data strongly indicate that the Gla domain contains four intermediate and five to six low affinity Ca2+-binding sites, whereas the EGF1 and the protease domains each contains one high affinity Ca2+-binding site. Further, proteolysis in the autolysis loop of the catalytic domain results in a virtual loss of amidolytic activity without affecting the S1 binding site. Autolysis loop-cleaved factor Xa (Xaγ) also has ∼10-fold reduced affinity for factor Va. Importantly, Ca2+ protects the proteolytic cleavage in the autolysis loop, thereby stabilizing this domain for maximal biologic activity. An initial account of this work has been presented in abstract form (10Sabharwal A.K. Welsh W.J. Saini R. Gorka J. Birktoft J.J. Bajaj S.P. Blood. 1993; 82 (Abstr. 245): 64aGoogle Scholar). Factor X is a vitamin K-dependent multidomain protein that participates in the middle phase of blood coagulation (1Davie E.W. Fujikawa K. Kisiel W. Biochemistry. 1991; 29: 10363-10370Crossref Scopus (1616) Google Scholar). Factor X is essential for hemostasis since a reduction in its functional activity results in a rare autosomal recessive bleeding disorder known as Stuart-Prower factor deficiency (2Graham J.B. Barrow E.M. Hougie C. J. Clin. Invest. 1957; 36: 497-503Crossref PubMed Scopus (47) Google Scholar). The human protein is synthesized in the liver as a precursor molecule of 488 amino acids (3Leytus S.P. Foster D.C. Kurachi K. Davie E.W. Biochemistry. 1986; 25: 5098-5102Crossref PubMed Scopus (182) Google Scholar). The amino-terminal 40 amino acids constitute the prepro leader sequence, which is removed prior to secretion of the molecule. Additionally, during biosynthesis, the protein undergoes several posttranslational modifications including glycosylation, γ-carboxylation (of the first 11 glutamic acid residues), β-hydroxylation (of Asp-63), and removal of a tripeptide (Arg-Lys-Arg) between Arg-139 and Ser-143 (3Leytus S.P. Foster D.C. Kurachi K. Davie E.W. Biochemistry. 1986; 25: 5098-5102Crossref PubMed Scopus (182) Google Scholar). The resulting mature protein is a zymogen of serine protease factor Xa and consists of a light chain (amino acids 1–139) and a heavy chain (amino acids 143–448) held together by a single disulfide bond between Cys-132 and Cys-302. Gene arrangement, amino acid sequence, and modular structure of factor X strongly suggest that the protein is organized into several distinct domains (3Leytus S.P. Foster D.C. Kurachi K. Davie E.W. Biochemistry. 1986; 25: 5098-5102Crossref PubMed Scopus (182) Google Scholar, 4Padmanabhan K. Padmanabhan K.P. Tulinsky A. Park C.H. Bode W. Huber R. Blankenship D.T. Cardin A.D. Kisiel W. J. Mol. Biol. 1993; 232: 947-966Crossref PubMed Scopus (401) Google Scholar). The amino terminus of the light chain contains 11 γ-carboxyglutamic acid (Gla) 1The abbreviations and trivial names used are: Gla, γ-carboxyglutamic acid; DEGR-CK, dansyl-Glu-Gly-Arg-chloromethyl ketone; EGF, epidermal growth factor; des-44-X or -Xa, Gla-domainless human factor X or Xa; PC, phosphatidylcholine; PS, phosphatidylserine; BSA, bovine serum albumin; PL, phospholipid; p-AB,p-aminobenzamidine; peptide 1, peptide containing the sequence of 238–277(59–97) residues of factor X; peptide 2, peptide containing the sequence of 238–262(58–82) of factor X; peptide 3, peptide containing the sequence of 253–277(73–97) of factor X; S-2222, benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide; S-2238, H-d-Phe-Pip-Arg-p-nitroanilide; DEGR-Xa, factor Xa inactivated with DEGR-CK; DEGR-des-44-Xa, des-44-Xa inactivated with DEGR-CK; TBS, Tris-buffered saline; IIa, α-thrombin; dansyl, 5-dimethylaminonaphthalene-1-sulfonyl.1The abbreviations and trivial names used are: Gla, γ-carboxyglutamic acid; DEGR-CK, dansyl-Glu-Gly-Arg-chloromethyl ketone; EGF, epidermal growth factor; des-44-X or -Xa, Gla-domainless human factor X or Xa; PC, phosphatidylcholine; PS, phosphatidylserine; BSA, bovine serum albumin; PL, phospholipid; p-AB,p-aminobenzamidine; peptide 1, peptide containing the sequence of 238–277(59–97) residues of factor X; peptide 2, peptide containing the sequence of 238–262(58–82) of factor X; peptide 3, peptide containing the sequence of 253–277(73–97) of factor X; S-2222, benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide; S-2238, H-d-Phe-Pip-Arg-p-nitroanilide; DEGR-Xa, factor Xa inactivated with DEGR-CK; DEGR-des-44-Xa, des-44-Xa inactivated with DEGR-CK; TBS, Tris-buffered saline; IIa, α-thrombin; dansyl, 5-dimethylaminonaphthalene-1-sulfonyl. residues and represents the Gla domain (residues 1–39) of factor X (3Leytus S.P. Foster D.C. Kurachi K. Davie E.W. Biochemistry. 1986; 25: 5098-5102Crossref PubMed Scopus (182) Google Scholar). The Gla domain is followed by a short hydrophobic stack (residues 40–45) and two epidermal growth factor (EGF)-like domains (residues 46–84 (EGF1) and residues 85–128 (EGF2)). The amino terminus of the heavy chain of factor X contains the activation peptide region of 52 amino acids (residues 143–194) followed by the serine protease domain of 254 amino acids (residues 195–448), which features the active site triad of His-236(57), 2For comparison, factor X amino acid numbering system has been used. The number in parentheses refers to the chymotrypsin equivalents for the protease domain of factor Xa.2For comparison, factor X amino acid numbering system has been used. The number in parentheses refers to the chymotrypsin equivalents for the protease domain of factor Xa. Asp-282(102), and Ser-379(195) (3Leytus S.P. Foster D.C. Kurachi K. Davie E.W. Biochemistry. 1986; 25: 5098-5102Crossref PubMed Scopus (182) Google Scholar). During physiologic hemostasis, factor X can be activated by factor IXa, requiring Ca2+, phospholipid (PL), and factor VIIIa or factor VIIa requiring Ca2+ and tissue factor (1Davie E.W. Fujikawa K. Kisiel W. Biochemistry. 1991; 29: 10363-10370Crossref Scopus (1616) Google Scholar, 5Bajaj M.S. Ameri A. Bajaj S.P. Green D. Anticoagulants: Physiologic, Pathologic, and Pharmacologic. CRC Press, Boca Raton, FL1994: 41-65Google Scholar). A potent nonphysiologic activator of factor X is the coagulant protein from Russell's viper venom (6Di Scipio R.G. Hermodson M.A. Davie E.W. Biochemistry. 1977; 16: 5253-5260Crossref PubMed Scopus (115) Google Scholar). In all cases, the activation results from the cleavage of the Arg-194–Ile-195(15–16) bond in the heavy chain of factor X and release of a 52-residue activation peptide; the light chain remains unaltered during this process (3Leytus S.P. Foster D.C. Kurachi K. Davie E.W. Biochemistry. 1986; 25: 5098-5102Crossref PubMed Scopus (182) Google Scholar, 7Leytus S.P. Chung D.W. Kisiel W. Kurachi K. Davie E.W. Proc. Natl. Acad. Sci. U. S. A. 1984; 81: 3699-3702Crossref PubMed Scopus (98) Google Scholar). Factors X and Xaα 3The nomenclature used for factor Xa is that of Di Scipio et al. (6Di Scipio R.G. Hermodson M.A. Davie E.W. Biochemistry. 1977; 16: 5253-5260Crossref PubMed Scopus (115) Google Scholar). Factor Xaα is factor Xa consisting of a light chain (L, amino acids 1–139) and a heavy chain (Hα, amino acids 195–448). Factor Xaβ is factor Xaα lacking the ∼4 kDa fragment from the COOH terminus of the Hα chain. Factor Xaγ is factor Xaβ in which proteolysis has occurred in the autolysis loop in the Hβ chain. Factor Xaβγ is a mixture of factors Xaβ and Xaγ.3The nomenclature used for factor Xa is that of Di Scipio et al. (6Di Scipio R.G. Hermodson M.A. Davie E.W. Biochemistry. 1977; 16: 5253-5260Crossref PubMed Scopus (115) Google Scholar). Factor Xaα is factor Xa consisting of a light chain (L, amino acids 1–139) and a heavy chain (Hα, amino acids 195–448). Factor Xaβ is factor Xaα lacking the ∼4 kDa fragment from the COOH terminus of the Hα chain. Factor Xaγ is factor Xaβ in which proteolysis has occurred in the autolysis loop in the Hβ chain. Factor Xaβγ is a mixture of factors Xaβ and Xaγ. can also be converted to their respective β-forms where ∼4 kDa peptide is cleaved off from the COOH terminus of the heavy chain; this, however, does not result in a loss of coagulant activity (6Di Scipio R.G. Hermodson M.A. Davie E.W. Biochemistry. 1977; 16: 5253-5260Crossref PubMed Scopus (115) Google Scholar). Factor Xa converts prothrombin to thrombin in the coagulation cascade; for a physiologically significant rate, this reaction requires Ca2+, PL, and factor Va (8Mann K.G. Nesheim M.E. Church W.R. Haley P. Krishnaswamy S. Blood. 1990; 76: 1-16Crossref PubMed Google Scholar). Thus, Ca2+ plays an important role both in the activation of factor X and in the conversion of prothrombin to thrombin by factor Xa. Ca2+ binding to human factor X has been studied by Monroeet al. (9Monroe D.M. Deerfield D.W., II Olson D.L. Stewart T.N. Treanor R.E. Roberts H.R. Hiskey R.G. Pedersen L.G. Blood Coagul. Fibrinolysis. 1990; 1: 633-640PubMed Google Scholar). The authors reported that the protein contains one high affinity Gla-independent and 19 weak Gla-dependent Ca2+-binding sites (9Monroe D.M. Deerfield D.W., II Olson D.L. Stewart T.N. Treanor R.E. Roberts H.R. Hiskey R.G. Pedersen L.G. Blood Coagul. Fibrinolysis. 1990; 1: 633-640PubMed Google Scholar). In the present report, we have extensively investigated the Ca2+-binding properties of native, decarboxylated, and Gla domainless (des-44-X) human factor X. The data strongly indicate that the Gla domain contains four intermediate and five to six low affinity Ca2+-binding sites, whereas the EGF1 and the protease domains each contains one high affinity Ca2+-binding site. Further, proteolysis in the autolysis loop of the catalytic domain results in a virtual loss of amidolytic activity without affecting the S1 binding site. Autolysis loop-cleaved factor Xa (Xaγ) also has ∼10-fold reduced affinity for factor Va. Importantly, Ca2+ protects the proteolytic cleavage in the autolysis loop, thereby stabilizing this domain for maximal biologic activity. An initial account of this work has been presented in abstract form (10Sabharwal A.K. Welsh W.J. Saini R. Gorka J. Birktoft J.J. Bajaj S.P. Blood. 1993; 82 (Abstr. 245): 64aGoogle Scholar)." @default.
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• W2000549605 date "1997-08-01" @default.
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• W2000549605 title "Interaction of Calcium with Native and Decarboxylated Human Factor X." @default.
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• W2000549605 doi "https://doi.org/10.1074/jbc.272.35.22037" @default.
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