Anchoring of Coagulation factor VIIa to the membrane through its GLA domain
Identifiers
Symbol
Gla
Pfam
PF00594
InterPro
IPR000294
PROSITE
PDOC00011
SCOP2
1cfi / SCOPe / SUPFAM
OPM superfamily
89
OPM protein
1pfx
Membranome
342
Available protein structures:
Pfam
structures / ECOD
PDB
RCSB PDB; PDBe; PDBj
PDBsum
structure summary
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), plus two proline-rich Gla-proteins (PRGPs) and two transmembrane Gla proteins (TMGPs), the functions of which are unknown.[6][7][8]
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.[9]
^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.
^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. Bibcode:1987PNAS...84.8335P. doi:10.1073/pnas.84.23.8335. PMC 299537. PMID 3317405.
^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.
^ abFreedman 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.
^Kulman JD, Harris JE, Haldeman BA, Davie EW (August 1997). "Primary structure and tissue distribution of two novel proline-rich gamma-carboxyglutamic acid proteins". Proc. Natl. Acad. Sci. U.S.A. 94 (17): 9058–62. Bibcode:1997PNAS...94.9058K. doi:10.1073/pnas.94.17.9058. PMC 23027. PMID 9256434.
^Cite error: The named reference Kulman2001 was invoked but never defined (see the help page).
^Cite error: The named reference Kulman2007 was invoked but never defined (see the help page).
^Suttie, J.W. (1993-03-01). "Synthesis of vitamin K-dependent proteins" (PDF). FASEB Journal. 7 (5). The Federation of American Societies for Experimental Biology: 445–52. doi:10.1096/fasebj.7.5.8462786. PMID 8462786. S2CID 805045. Retrieved 2014-11-17.
Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain is a protein domain that contains post-translational modifications of many glutamate...
γ-carboxyglutamate residues are present in the γ-carboxyglutamic acid-rich ("GLA") domain. This GLAdomain is known to be found in over a dozen known proteins, including...
gamma-carboxyglutamate (Gla) residues. The modified residues are often (but not always) situated within specific protein domains called Gladomains. Gla residues are...
a glycoside hydrolase enzyme GLA (gene), an encoding of the enzyme alpha-galactosidase A Gladomain, a protein domain Gamma-Linolenic acid, a fatty acid...
a common domain architecture. The factor IX protein is composed of four protein domains: the Gladomain, two tandem copies of the EGF domain and a C-terminal...
first identified as a calcium-binding protein. Because osteocalcin has gladomains, its synthesis is vitamin K dependent. In humans, osteocalcin is encoded...
S has a peptide between the Gladomain and the EGF-like domain, that is cleaved by thrombin. The Gla and EGF-like domains stay connected after the cleavage...
vitamin K-dependent procoagulant factors dock to this surface through their Gladomain with Ca2+ bridges. Undas, A.; Brummel-Ziedins, K. E.; Mann, K. G. (29...
protease domain (212–450). The light chain contains the Gla- and EGF-like domains and the aromatic segment. The heavy chain contains the protease domain and...
to support adhesion and migration of epithelial cells. Periostin is a gladomain vitamin K dependent factor. Periostin is a secreted extracellular matrix...
carboxylation of the gladomain in "Gla proteins" (i.e., in conversion of peptide-bound glutamic acid (Glu) to γ-carboxy glutamic acid (Gla) in these proteins)...
is composed of four domains; an N-terminal Gladomain, two kringle domains and a C-terminal trypsin-like serine protease domain. Factor Xa with factor...
native FXa due to the removal of a 34 residue fragment that contains the Gladomain. This modification reduces andexanet alfa's anticoagulant potential. Additionally...
functions to inhibit blood coagulation by binding to an inhibitor. It is a GLAdomain protein and thus Vitamin K-dependent, and its functionality is therefore...
Kringle domains are autonomous protein domains that fold into large loops stabilized by 3 disulfide linkages. These are important in protein–protein interactions...
Chin (2014-08-01). "Structural Insights into Calcium-Bound S100P and the V Domain of the RAGE Complex". PLOS ONE. 9 (8): e103947. Bibcode:2014PLoSO...9j3947P...
brains of patients with schizophrenia. Transthyretin is known to contain a Gladomain, and thus be dependent for production on post-translational modification...
acidic protein residues and phosphate groups of lipids, as in annexins or GLAdomains. These peripheral proteins function as carriers of non-polar compounds...
NM, Kurzydlowski K, Tada M, MacLennan DH (August 2001). "Phospholamban domain IB forms an interaction site with the loop between transmembrane helices...
regulatory domains to the pore. The RyR1 pore architecture shares the general structure of the six-transmembrane ion channel superfamily. A unique domain inserted...
for its high-capacity to bind Ca2+. In addition, the hydrophobic core of domain II appears to be necessary for CASQ2's function, because a single amino...
and a C lobe. The C lobe serves a structural purpose and binds to the N domain of troponin I (TnI). The C lobe can bind either Ca2+ or Mg2+. The N lobe...
fluorescence microscope. Annexin A5 has been shown to interact with Kinase insert domain receptor and Integrin, beta 5. GRCh38: Ensembl release 89: ENSG00000164111...
kDa). The protein has two approximately symmetrical globular domains (the N- and C- domains) each containing a pair of EF hand motifs separated by a flexible...
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