Factor Xa: Difference between revisions
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===Light Chain=== | ===Light Chain=== | ||
The factor Xa light chain contains a γ-carboxyglutamic acid | The factor Xa light chain contains a γ-carboxyglutamic acid (Gla) domain [http://en.wikipedia.org/wiki/Gla_domain γ-carboxyglutamic acid (Gla)](11 gla residues) as well as two epidermial growth factor (EGF)-like domains [http://en.wikipedia.org/wiki/Epidermal_growth_factor epidermal growth factor (EGF)].<ref name="EGF">PMID:8355279</ref> Vitamin K-dependent <scene name='Factor_Xa/Transparent_-_no_inhib_gla/1'>GLA</scene> domain is a protein domain that contains post-translational modifications of many glutamate residues by vitamin K-dependent carboxylation to form gamma-carboxyglutamate. <ref name="GLA1">PMID:3106112</ref> <ref name="Gla2">PMID:2183788</ref> This domain begins at the N-terminus of the protein and ends with a conserved aromatic residue. There is also a conserved Gla-X(3)-Gla-X-Cys motif <ref name="GLA seq">PMID: 3317405</ref>, located in the middle of the GLA domain, and appears to be important for recognition by the vitamin K-dependent carboxylase. The Gla residues are responsible for the high-affinity binding of calcium ions. Based on 3D structures of several Gla domains it that the binding of calcium ions induce conformational changes in the domain and are necessary for proper folding of this region. <ref name="GLA Cal">PMID 7713897</ref>A common structural feature of Gla domains is the clustering of N-terminal hydrophobic residues into a hydrophobic patch that mediates interaction with the cell surface membrane. <ref name="GLA struct">PMID 8663165</ref> The Gla domain enables factor X/Xa to bind phospholipid (i.e. cell surfaces) in a calcium dependent manner; a requirement for assembly of the prothrombinase complex. Factor Xa from which the Gla domain has been removed by limited chymotryptic digestion does not bind to phospholipid-factor Va and is virtually inactive. <ref> PMID: 3512564 </ref> | ||
EGF-like domains have a length of approximately 40 amino acids and are characterized by a conserved arrangement of six cysteine residues that form 3 evenly spaced disulfide bonds.<ref> PMID: 2116263</ref> Factor X contains two of them located between the membrane-proximal γ-carboxyglutamic acid (Gla)- containing domain and the serine protease domain. The first EGF-like domain in these proteins contains 1 Ca2+ binding site. <ref> PMID: 3259233</ref> The side chains of two Asp, one of which may be β-hydroxylated, and one Gln residue and two backbone carbonyl oxygens have been identified as Ca2+ ligands in the first EGF-like domain. <ref> PMID: 1527084 </ref> The affinity of this site in factor X is represented by a dissociation constant (Kd) of about 0.1 mM in the intact protein. <ref>PMID: 8226763 </ref> In contrast, Ca2+ binding to the isolated EGF-like domain has a 20-fold higher Kd <ref> PMID: 2789221 </ref>. The biological function of EGF-like domains are largely unknown, some proteins containing them, may have some EGF-like functions also. Recent crystal structures suggest that the N-terminal epidermal growth factor (EGF)-like domain is flexibly, while the second EGF domain maintains contacts with the catalytic domain. | EGF-like domains have a length of approximately 40 amino acids and are characterized by a conserved arrangement of six cysteine residues that form 3 evenly spaced disulfide bonds.<ref> PMID: 2116263</ref> Factor X contains two of them located between the membrane-proximal γ-carboxyglutamic acid (Gla)- containing domain and the serine protease domain. The first EGF-like domain in these proteins contains 1 Ca2+ binding site. <ref> PMID: 3259233</ref> The side chains of two Asp, one of which may be β-hydroxylated, and one Gln residue and two backbone carbonyl oxygens have been identified as Ca2+ ligands in the first EGF-like domain. <ref> PMID: 1527084 </ref> The affinity of this site in factor X is represented by a dissociation constant (Kd) of about 0.1 mM in the intact protein. <ref>PMID: 8226763 </ref> In contrast, Ca2+ binding to the isolated EGF-like domain has a 20-fold higher Kd <ref> PMID: 2789221 </ref>. The biological function of EGF-like domains are largely unknown, some proteins containing them, may have some EGF-like functions also. Recent crystal structures suggest that the N-terminal epidermal growth factor (EGF)-like domain is flexibly, while the second EGF domain maintains contacts with the catalytic domain. | ||
