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68  structures 220  species 0  interactions 3313  sequences 119  architectures

Family: Gla (PF00594)

Summary: Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain

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Gla domain Edit Wikipedia article

GLA Domain
1dan opm.png
Anchoring of Coagulation factor VIIa to the membrane through its GLA domain
OPM superfamily89
OPM protein1pfx

Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain is a protein domain that contains post-translational modifications of many glutamate residues by vitamin K-dependent carboxylation to form γ-carboxyglutamate (Gla). Proteins with this domain are known informally as Gla proteins. The Gla residues are responsible for the high-affinity binding of calcium ions.[1][2]

The GLA domain binds calcium ions by chelating them between two carboxylic acid residues. These residues are part of a region that starts at the N-terminal extremity of the mature form of Gla proteins, and that ends with a conserved aromatic residue. This results in a conserved Gla-x(3)-Gla-x-Cys motif[3] that is found in the middle of the domain, and which seems to be important for substrate recognition by the carboxylase.

The 3D structures of several Gla domains have been solved.[4][5] 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.[5]

At present, the following human Gla-containing proteins (Gla proteins) have been characterized to the level of primary structure: the blood coagulation factors II (prothrombin), VII, IX, and X, the anticoagulant proteins C and S, and the factor X-targeting protein Z. The bone Gla protein osteocalcin, the calcification-inhibiting matrix Gla protein (MGP), the cell growth regulating "growth arrest specific gene 6" protein GAS6, periostin (a factor necessary for migration and adhesion of epithelial cells), two transmembrane Gla proteins (TMGPs), and two proline-rich Gla-proteins (PRGPs), the function of which at present are unknown.

In all cases in which their function was known, the presence of the Gla residues in these proteins turned out to be essential for functional activity.[6]


Human proteins containing this domain

Only major, known functions are listed in this list; knowledge about these is not complete.

  1. Thrombin (F2) (a.k.a. coagulation factor II; also its precursor prothrombin) – involved in coagulation
  2. Factor VII (F7) – involved in coagulation
  3. Factor IX (F9) – involved in coagulation
  4. Factor X (F10) – involved in coagulation
  5. Protein C (PROC) – roles in regulating anticoagulation, inflammation, cell death, and maintaining the permeability of blood vessel walls
  6. Protein S (PROS1) – involved in coagulation
  7. Protein Z (PROZ) – involved in coagulation
  8. Osteocalcin (BGLAP) – involved in bone mineralization.
  9. Matrix gla protein (MGP) – inhibitor of calcification of soft tissue and plays a role in bone organization
  10. GAS6 – thought to be involved in the stimulation of cell proliferation
  11. Transthyretin (TTR) previously known as prealbumin – carries thyroxine (T4) in blood and into cerebral spinal fluid
  12. Inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2) – plays a role in pancreas islets and many other cells
  13. Periostin – a factor necessary for cell migration (embryonic development, and immune responses) and adhesion of epithelial cells, over-expressed in some cancers
  14. Proline rich gla 1 (PRRG1)
  15. Proline rich gla 2 (PRRG2)
  16. Proline rich gla 3 (PRRG3)
  17. Proline rich gla 4 (PRRG4)


  1. ^ Friedman PA, Przysiecki CT (1987). "Vitamin K-dependent carboxylation". Int. J. Biochem. 19 (1): 1–7. doi:10.1016/0020-711X(87)90116-9. PMID 3106112.
  2. ^ Vermeer C (1990). "Gamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase". Biochem. J. 266 (3): 625–636. doi:10.1042/bj2660625. PMC 1131186. PMID 2183788.
  3. ^ Price PA, Fraser JD, Metz-Virca G (1987). "Molecular cloning of matrix Gla protein: implications for substrate recognition by the vitamin K-dependent gamma-carboxylase". Proc. Natl. Acad. Sci. U.S.A. 84 (23): 8335–8339. doi:10.1073/pnas.84.23.8335. PMC 299537. PMID 3317405.
  4. ^ Freedman SJ, Furie BC, Furie B, Baleja JD (1995). "Structure of the metal-free gamma-carboxyglutamic acid-rich membrane binding region of factor IX by two-dimensional NMR spectroscopy". J. Biol. Chem. 270 (14): 7980–7987. doi:10.1074/jbc.270.14.7980. PMID 7713897.
  5. ^ a b Freedman SJ, Furie BC, Furie B, Baleja JD, Blostein MD, Jacobs M (1996). "Identification of the phospholipid binding site in the vitamin K-dependent blood coagulation protein factor IX". J. Biol. Chem. 271 (27): 16227–16236. doi:10.1074/jbc.271.27.16227. PMID 8663165.
  6. ^ Suttie, J.W. (1993-03-01). "Synthesis of vitamin K-dependent proteins" (PDF). The FASEB Journal. The Federation of American Societies for Experimental Biology. Retrieved 2014-11-17.

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain Provide feedback

This domain is responsible for the high-affinity binding of calcium ions. This domain contains post-translational modifications of many glutamate residues by Vitamin K-dependent carboxylation to form gamma-carboxyglutamate (Gla).

Literature references

  1. Freedman SJ, Furie BC, Furie B, Baleja JD; , Biochemistry 1995;34:12126-12137.: Structure of the calcium ion-bound gamma-carboxyglutamic acid-rich domain of factor IX. PUBMED:7547952 EPMC:7547952

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000294

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) [ PUBMED:18374189 , PUBMED:11818531 , PUBMED:18374194 ]. 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.

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 [ PUBMED:3317405 ] is found in the middle of the domain which seems to be important for substrate recognition by the carboxylase.

The 3D structure of the GLA domain has been solved [ PUBMED:7713897 , PUBMED:8663165 ]. 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 [ PUBMED:8663165 ].

Proteins known to contain a GLA domain include [ PUBMED:18373251 ]:

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan EGF (CL0001), which has the following description:

Members of this clan all belong to the EGF superfamily. This particular superfamily is characterised as having least 6 cysteine residues. These cysteines form disulphide bonds, in the order 1-3, 2-4, 5-6, which are essential for the stability of the EGF fold. These disulphide bonds are stacked in a ladder-like arrangement. The Laminin EGF family is distinguished by having an an additional disulphide bond. The function of the domains within this family remains unclear, but they are thought to largely perform a structural role. More often than not, these domains are arranged in tandem repeats in extracellular proteins.

The clan contains the following 22 members:

cEGF CFC DSL EGF EGF_2 EGF_3 EGF_alliinase EGF_CA EGF_MSP1_1 EGF_Tenascin Ephrin_rec_like Fibrillin_U_N FOLN FXa_inhibition Gla hEGF I-EGF_1 Laminin_EGF Plasmod_Pvs28 Sushi Sushi_2 Tme5_EGF_like


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Seed source: Prosite.
Previous IDs: gla;
Type: Domain
Sequence Ontology: SO:0000417
Author: Bateman A
Number in seed: 89
Number in full: 3313
Average length of the domain: 40.10 aa
Average identity of full alignment: 58 %
Average coverage of the sequence by the domain: 9.06 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.4 20.4
Trusted cut-off 20.4 20.4
Noise cut-off 19.8 19.8
Model length: 41
Family (HMM) version: 22
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Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Gla domain has been found. There are 68 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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