Gla‐Domain

Abstract

The term ‘Gla‐domain’ is used to describe the γ‐carboxyglutamic acid (Gla)‐containing region of certain vitamin K–dependent proteins such as prothrombin and factor IX. The domain comprises the first 45 or so amino acids at the N‐terminus of these proteins and contains 9–13 Gla residues that can bind divalent metal cations in a cooperative manner, the most physiologically important being Ca 2+ . Binding of Ca 2+ by the Gla residues induces a conformational transition in the domain that allows it to bind to phospholipid‐containing membranes, a requisite step for the biological functioning of the proteins. Gla residues are also found in two proteins of bone and the extracellular matrix (bone Gla protein or osteocalcin, and matrix Gla protein), and in neurotoxic peptides synthesized by molluscs of the genus Conus , but these polypeptides are not considered to have a Gla‐domain as such, and will not be discussed here.

Post-translational modifications in proteins involved in blood coagulation

“…The structure showed that the α ‐helices were retained, albeit less well defined than in the Ca 2+ ‐saturated form. However, the N‐terminal 11 residues were very mobile, with the two Gla residues exposed to solvent and the three hydrophobic residues (Phe4, Leu5, and Val8) clustered in the interior of the domain [45,74]. Similar results were obtained by NMR studies of a synthetic Gla domain from FIX [75].…”

“…In vertebrates most vitamin K‐dependent proteins are coagulation factors that all have an N‐terminal so‐called Gla domain that is about 45 amino acid residues long and contains from 9 to 12 Gla residues (Fig. 4A, Table 1) [22,45]. The Gla domain is found in prothrombin and FVII, FIX, FX, which all belong to the traditional coagulation system.…”

“…Coupled to this conformational change is the translocation of Phe5, Leu6, and Val9 from inside the domain to a position on the surface, where the side chains are exposed to the solvent. The Ca 2+ ‐induced structural transition brings Gla carboxylate groups into close proximity and hence electrostatic repulsion calls for highly cooperative metal ion binding [45].…”

Precursors of Novel Gla-Containing Conotoxins Contain a Carboxy-Terminal Recognition Site That Directs γ-Carboxylation,

“…In most of the vertebrate vitamin K-dependent proteins, 10−13 Glu residues are modified by the γ-carboxylase. These reside within an ∼45-residue stretch, termed the Gla domain, that is located at the N-terminus of the mature polypeptide ( , ). Osteocalcin and matrix Gla protein are exceptions in that they do not have a Gla domain, and only 3−5 Glu residues become γ-carboxylated.…”