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PROSITE documentation PDOC00011Gamma-carboxyglutamic acid-rich (Gla) domain signature and profile
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PURL: https://purl.expasy.org/prosite/documentation/PDOC00011
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: Last update:June 2004 / Pattern and text revised; profile added.
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PROSITE methods (with tools and information) covered by this documentation:
| 1 | Authors | Friedman P.A. Przysiecki C.T. |
| Title | Vitamin K-dependent carboxylation. | |
| Source | Int. J. Biochem. 19:1-7(1987). | |
| PubMed ID | 3106112 |
| 2 | Authors | Vermeer C. |
| Title | Gamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. | |
| Source | Biochem. J. 266:625-636(1990). | |
| PubMed ID | 2183788 |
| 3 | Authors | Freedman S.J. Furie B.C. Furie B. Baleja J.D. |
| Title | Structure of the metal-free gamma-carboxyglutamic acid-rich membrane binding region of factor IX by two-dimensional NMR spectroscopy. | |
| Source | J. Biol. Chem. 270:7980-7987(1995). | |
| PubMed ID | 7713897 |
| 4 | Authors | Freedman S.J. Blostein M.D. Baleja J.D. Jacobs M. Furie B.C. Furie B. |
| Title | Identification of the phospholipid binding site in the vitamin K-dependent blood coagulation protein factor IX. | |
| Source | J. Biol. Chem. 271:16227-16236(1996). | |
| PubMed ID | 8663165 |
| 5 | Authors | Kulman J.D. Harris J.E. Haldeman B.A. Davie E.W. |
| Title | Primary structure and tissue distribution of two novel proline-rich gamma-carboxyglutamic acid proteins. | |
| Source | Proc. Natl. Acad. Sci. U.S.A. 94:9058-9062(1997). | |
| PubMed ID | 9256434 |
| 6 | Authors | Haack J.A. Rivier J.E. Parks T.N. Mena E.E. Cruz L.J. Olivera B.M. |
| Title | Conantokin-T. A gamma-carboxyglutamate containing peptide with N-methyl-d-aspartate antagonist activity. | |
| Source | J. Biol. Chem. 265:6025-6029(1990). | |
| PubMed ID | 2180939 |
| 7 | Authors | Price P.A. Fraser J.D. Metz-Virca G. |
| Title | Molecular cloning of matrix Gla protein: implications for substrate recognition by the vitamin K-dependent gamma-carboxylase. | |
| Source | Proc. Natl. Acad. Sci. U.S.A. 84:8335-8339(1987). | |
| PubMed ID | 3317405 |
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