PROSITE documentation PDOC00011 [for PROSITE entry PS50998]

Gamma-carboxyglutamic acid-rich (Gla) domain signature and profile




Description

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).
  • Proline-rich Gla proteins 1 and 2 [5].
  • 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.

Expert(s) to contact by email:

Price P.A.

Last update:

June 2004 / Pattern and text revised; profile added.

Technical section

PROSITE methods (with tools and information) covered by this documentation:

GLA_2, PS50998; Gla domain profile  (MATRIX)

GLA_1, PS00011; Vitamin K-dependent carboxylation domain  (PATTERN)


References

1AuthorsFriedman P.A., Przysiecki C.T.
TitleVitamin K-dependent carboxylation.
SourceInt. J. Biochem. 19:1-7(1987).
PubMed ID3106112

2AuthorsVermeer C.
TitleGamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase.
SourceBiochem. J. 266:625-636(1990).
PubMed ID2183788

3AuthorsFreedman S.J., Furie B.C., Furie B., Baleja J.D.
TitleStructure of the metal-free gamma-carboxyglutamic acid-rich membrane binding region of factor IX by two-dimensional NMR spectroscopy.
SourceJ. Biol. Chem. 270:7980-7987(1995).
PubMed ID7713897

4AuthorsFreedman S.J., Blostein M.D., Baleja J.D., Jacobs M., Furie B.C., Furie B.
TitleIdentification of the phospholipid binding site in the vitamin K-dependent blood coagulation protein factor IX.
SourceJ. Biol. Chem. 271:16227-16236(1996).
PubMed ID8663165

5AuthorsKulman J.D., Harris J.E., Haldeman B.A., Davie E.W.
TitlePrimary structure and tissue distribution of two novel proline-rich gamma-carboxyglutamic acid proteins.
SourceProc. Natl. Acad. Sci. U.S.A. 94:9058-9062(1997).
PubMed ID9256434

6AuthorsHaack J.A., Rivier J.E., Parks T.N., Mena E.E., Cruz L.J., Olivera B.M.
TitleConantokin-T. A gamma-carboxyglutamate containing peptide with N-methyl-d-aspartate antagonist activity.
SourceJ. Biol. Chem. 265:6025-6029(1990).
PubMed ID2180939

7AuthorsPrice P.A., Fraser J.D., Metz-Virca G.
TitleMolecular cloning of matrix Gla protein: implications for substrate recognition by the vitamin K-dependent gamma-carboxylase.
SourceProc. Natl. Acad. Sci. U.S.A. 84:8335-8339(1987).
PubMed ID3317405



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