The vitamin K-dependent blood coagulation factor IX as well as several
extracellular regulatory proteins require vitamin K for the posttranslational
synthesis of γ-carboxyglutamic acid, an amino acid clustered in the
N-terminal Gla domain of these proteins [1,2]. The Gla domain is a membrane
binding motif which, in the presence of calcium ions, interacts with
phospholipid membranes that include phosphatidylserine.
The 3D structure of the Gla domain has been solved (see for example
<PDB:1CFH>) [3,4]. Calcium ions induce conformational changes in the Gla
domain and are necessary for the Gla domain to fold properly. 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 [4].
Proteins known to contain a Gla domain are listed below:
A number of plasma proteins involved in blood coagulation. These proteins
are prothrombin, coagulation factors VII, IX and X, proteins C, S, and Z.
Two proteins that occur in calcified tissues: osteocalcin (also known as
bone-Gla protein, BGP), and matrix Gla-protein (MGP).
Cone snail venom peptides: conantokin-G and -T, and conotoxin GS [6].
The pattern we developed start with the conserved Gla-x(3)-Gla-x-Cys motif
found in the middle of the domain which seems to be important for substrate
recognition by the carboxylase [7] and end with the last conserved position of
the domain (an aromatic residue). We also developed a profile that covers the
whole Gla domain.
Note:
All glutamic residues present in the domain are potential carboxylation
sites; in coagulation proteins, all are modified to Gla, while in BGP and MGP
some are not.
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