Factor IX: Difference between revisions
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The Gla domain of Factor IX consists of an N-terminal loop and three short ''ω''-<scene name='Factor_IX/Antifactor_2/3'>helixes</scene>(helix A: residues 14-19; helix B: residues 24-32; helix C: residues 35-45). The calcium ions are positioned between the loop and the A and B helices with calcium liganding providing the folding energy to align the loop properly. Helices A and B are connected by a tight turn and further stabilized by a conserved disulfide bond between residues 18 and 23 of the Gla domain. The two cysteine residues also form two hydrogen bonds (Tyr-45 to Cys-18, 3.10 Å; Tyr-45 to Cys-23, 2.88 Å) to the side chain of a conserved Tyr-45 of helix C, providing an anchor to bundle three helices together. This tyrosine residue and the disulfide bond are part of the hydrophobic core between helix C and helix A/B that includes Phe-25, Ala-28, Phe-41, and Trp-42, a cluster that provides further hydrophobic energy to bind helix C to helix A/B. All of these residues are conserved among Gla domains of vitamin K-dependent proteins. | The Gla domain of Factor IX consists of an N-terminal loop and three short ''ω''-<scene name='Factor_IX/Antifactor_2/3'>helixes</scene>(helix A: residues 14-19; helix B: residues 24-32; helix C: residues 35-45). The calcium ions are positioned between the loop and the A and B helices with calcium liganding providing the folding energy to align the loop properly. Helices A and B are connected by a tight turn and further stabilized by a conserved disulfide bond between residues 18 and 23 of the Gla domain. The two cysteine residues also form two hydrogen bonds (Tyr-45 to Cys-18, 3.10 Å; Tyr-45 to Cys-23, 2.88 Å) to the side chain of a conserved Tyr-45 of helix C, providing an anchor to bundle three helices together. This tyrosine residue and the disulfide bond are part of the hydrophobic core between helix C and helix A/B that includes Phe-25, Ala-28, Phe-41, and Trp-42, a cluster that provides further hydrophobic energy to bind helix C to helix A/B. All of these residues are conserved among Gla domains of vitamin K-dependent proteins. | ||
The binding of FIX to the phospholipid membrane is carried out by the loop, in the N terminus of the Gla domain. Four Ca2+ ions from Ca-2 to Ca-5 are essential to stabilize the ''ω''-loop region for membrane-binding <ref>PMID:8069632</ref> because these Ca2+ ions bind to conserved Gla7 and Gla8 residues in this region. The replacement by Mg2+ ions may lead to destabilization of the structure of the Gla domain, particularly in this region because of significant differences that exist with Ca2+ ion in both coordination distance and coordination sphere (Mg2+ ion takes generally a typical bipyramidal configuration and six coordination). This may explain why the Ca2+ ions are not replaced by Mg2+ ions in the present structure. | The binding of FIX to the phospholipid membrane is carried out by the loop, in the N terminus of the Gla domain. Four Ca2+ ions from Ca-2 to Ca-5 are essential to stabilize the ''ω''-loop region for membrane-binding <ref>PMID:8069632</ref> because these Ca2+ ions bind to conserved Gla7 and Gla8 residues in this region. The replacement by Mg2+ ions may lead to destabilization of the structure of the Gla domain, particularly in this region because of significant differences that exist with Ca2+ ion in both coordination distance and coordination sphere (Mg2+ ion takes generally a typical bipyramidal configuration and six coordination). This may explain why the Ca2+ ions are not replaced by Mg2+ ions in the present structure. | ||
The interaction of the Gla domain with the phospholipid membrane is carried out by binding to phosphatidylserine in the membrane through the interaction of calcium ions. Upon calcium binding to FIX a conformational change occurs in the Gla domain through the clustering of N-terminal hydrophobic residues into a hydrophobic patch, which is then exposed to the solvent. This hydrophobic patch then allows the association of the Gla domain with the cell surface membrane through electrostatic interactions between the phosphoserine head group and arginine and lysine residues in the Gla domain. The basic amino acid residues of factor IX (Lys-5 and Arg-10) bind to the glycerol phosphate backbone and the carboxyl group of the serine interacts with Ca-5 and Ca-6<ref>PMID:500729</ref> allowing membrane association. | The interaction of the Gla domain with the phospholipid membrane is carried out by binding to phosphatidylserine in the membrane through the interaction of calcium ions. Upon calcium binding to FIX a conformational change occurs in the Gla domain through the clustering of N-terminal hydrophobic residues into a hydrophobic patch, which is then exposed to the solvent. This hydrophobic patch then allows the association of the Gla domain with the cell surface membrane through electrostatic interactions between the phosphoserine head group and arginine and lysine residues in the Gla domain. The basic amino acid residues of factor IX (Lys-5 and Arg-10) bind to the glycerol phosphate backbone and the carboxyl group of the serine interacts with Ca-5 and Ca-6<ref>PMID:500729</ref> allowing membrane association. | ||
