<p>The GLA (gamma-carboxyglutamic acid-rich) domain contains glutamate residues that have been post-translationally modified by vitamin K-dependent carboxylation to form gamma-carboxyglutamate (Gla) [<cite idref="PUB00044565"/>, <cite idref="PUB00044566"/>, <cite idref="PUB00044567"/>]. All glutamic acid (Glu) residues present in the GLA domain are potential carboxylation sites; in coagulation proteins, all Gu residues are modified to Gla, while in osteocalcin and matrix Gla proteins only some Glu residues are modified to Gla. </p><p>The GLA domain is responsible for the high-affinity binding of calcium ions. It starts at the N-terminal extremity of the mature form of proteins and ends with a conserved aromatic residue; a conserved Gla-x(3)-Gla-x-Cys motif [<cite idref="PUB00004648"/>] is found in the middle of the domain which seems to be important for substrate recognition by the carboxylase.</p><p>The 3D structure of the GLA domain has been solved [<cite idref="PUB00015411"/>, <cite idref="PUB00015412"/>]. Calcium ions induce conformational changes in the GLA domain that and are necessary for the proper folding of the GLA domain. A common structural feature of functional GLA domains is the clustering of N-terminal hydrophobic residues into a hydrophobic patch that mediates interaction with the cell surface membrane [<cite idref="PUB00015412"/>]. </p><p>Proteins known to contain a GLA domain include [<cite idref="PUB00044568"/>]:</p><p> <ul><li> Coagulation factor X [<cite idref="PUB00044569"/>]</li><li> Coagulation factor VII [<cite idref="PUB00044570"/>]</li><li> Coagulation factor IX [<cite idref="PUB00044571"/>]</li><li> Coagulation factor XIV (vitamin K-dependent protein C) [<cite idref="PUB00044572"/>]</li><li> Vitamin K-dependent protein S [<cite idref="PUB00044573"/>]</li><li> Vitamin K-dependent protein Z [<cite idref="PUB00044574"/>]</li><li> Prothrombin</li><li> Transthyretin</li><li> Osteocalcin (also known as bone-Gla protein, BGP)</li><li> Matrix Gla protein (MGP) [<cite idref="PUB00044575"/>]</li><li> Inter-alpha-trypsin inhibitor heavy chain H2</li><li>Growth arrest-specific protein 6 (Gas-6) [<cite idref="PUB00044576"/>]</li></ul> </p> Gamma-carboxyglutamic acid-rich (GLA) domain