Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain is a

protein domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...

that contains post-translational modifications of many glutamate residues by

vitamin K Vitamin K is a family of structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-translational modification, post-synthesis modification of certain proteins ...

-dependent

carboxylation Carboxylation is a chemical reaction in which a carboxylic acid is produced by treating a substrate with carbon dioxide. The opposite reaction is decarboxylation. In chemistry, the term carbonation is sometimes used synonymously with 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. The GLA domain binds calcium ions by chelating them between two

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...

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 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. 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. 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 Protein Z (PZ or PROZ), vitamin K-dependent protein Z, is a protein encoded in the human by the ''PROZ'' gene. Protein Z is a member of the coagulation cascade, the group of blood proteins that leads to the formation of blood clots. It is a gly ...

. The bone Gla protein

osteocalcin Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a small (49-amino-acid) noncollagenous protein hormone found in bone and dentin, first identified as a calcium-binding protein. Because osteocalcin has ...

, the calcification-inhibiting matrix Gla protein (MGP), the

cell growth Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...

regulating "growth arrest specific gene 6" protein

GAS6 Growth arrest – specific 6, also known as GAS6, is a human gene coding for the GAS6 protein. It is similar to the Protein S with the same domain organization and 43% amino acid identity. It was originally found as a gene upregulated by growth a ...

periostin Periostin (POSTN, PN, or osteoblast-specific factor OSF-2) is a protein that in humans is encoded by the ''POSTN'' gene. Periostin functions as a ligand for alpha-v beta-3, alpha-V/beta-3 and alpha-v beta-5, alpha-V/beta-5 integrins to support c ...

(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. 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.

Subfamilies

Coagulation factor Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulation ...

, Gla region

Human proteins containing this domain

Thrombin Prothrombin (coagulation factor II) is encoded in the human by the F2-gene. It is proteolytically cleaved during the clotting process by the prothrombinase enzyme complex to form thrombin. Thrombin (Factor IIa) (, fibrose, thrombase, throm ...

(F2) (a.k.a. coagulation factor II; also its precursor prothrombin) – involved in

coagulation Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a thrombus, blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of co ...

Factor VII Coagulation factor VII (, formerly known as proconvertin) is a protein involved in coagulation and, in humans, is encoded by gene ''F7''. It is an enzyme of the serine protease class. Once bound to tissue factor released from damaged tissues, ...

(F7) – involved in coagulation #

Factor IX Factor IX (), also known as Christmas factor, is one of the serine proteases involved in coagulation; it belongs to peptidase family S1. Deficiency of this protein causes haemophilia B. It was discovered in 1952 after a young boy named Stephen ...

(F9) – involved in coagulation #

Factor X Coagulation factor X (), or Stuart factor, is an enzyme of the coagulation cascade, encoded in humans by ''F10'' gene. It is a serine endopeptidase (protease group S1, PA clan). Factor X is synthesized in the liver and requires vitamin K for i ...

(F10) – involved in coagulation #

Protein C Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and cell death and maintaini ...

(PROC) – roles in regulating

anticoagulation An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which h ...

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as di ...

, and maintaining the permeability of blood vessel walls #

Protein S Protein S (also known as PROS) is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In h ...

(PROS1) – involved in coagulation #

Protein Z Protein Z (PZ or PROZ), vitamin K-dependent protein Z, is a protein encoded in the human by the ''PROZ'' gene. Protein Z is a member of the coagulation cascade, the group of blood proteins that leads to the formation of blood clots. It is a gly ...

(PROZ) – involved in coagulation #

Osteocalcin Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a small (49-amino-acid) noncollagenous protein hormone found in bone and dentin, first identified as a calcium-binding protein. Because osteocalcin has ...

(BGLAP) – involved in

bone mineralization Biomineralization, also written biomineralisation, is the process by which living organisms produce minerals, often resulting in hardened or stiffened ''mineralized tissues''. It is an extremely widespread phenomenon: all six taxonomic kingdo ...

. # Matrix gla protein (MGP) – inhibitor of

calcification Calcification is the accumulation of calcium salts in a body tissue. It normally occurs in the formation of bone, but calcium can be deposited abnormally in soft tissue,Miller, J. D. Cardiovascular calcification: Orbicular origins. ''Nature M ...

of soft tissue and plays a role in bone organization #

– thought to be involved in the stimulation of cell proliferation #

Transthyretin Transthyretin (TTR or TBPA) is a transport protein in the plasma and cerebrospinal fluid that transports the thyroid hormone thyroxine (T4) and retinol to the liver. This is how transthyretin gained its name: ''transports thyroxine and retinol' ...

(TTR) previously known as prealbumin — carries thyroxine (T4) in blood and into cerebral spinal fluid #

Inter-alpha-trypsin inhibitor Inter-alpha-trypsin inhibitors (IαI) are plasma proteins consisting of three of four heavy chains selected from the group ITIH1, ITIH2, ITIH3, ITIH4 and one light chain selected from the group AMBP or SPINT2. They function as protease inhibit ...

heavy chain H2 (

ITIH2 Inter-alpha-trypsin inhibitor heavy chain H2 is a protein that in humans is encoded by the ''ITIH2'' gene. It is known to contain a Gla domain, and thus be dependent for production on post translational modification requiring vitamin K. Its funct ...

) – plays a role in pancreas islets and many other cells #

Periostin Periostin (POSTN, PN, or osteoblast-specific factor OSF-2) is a protein that in humans is encoded by the ''POSTN'' gene. Periostin functions as a ligand for alpha-v beta-3, alpha-V/beta-3 and alpha-v beta-5, alpha-V/beta-5 integrins to support c ...

– a factor necessary for cell migration (

embryonic development In developmental biology, animal embryonic development, also known as animal embryogenesis, is the developmental stage of an animal embryo. Embryonic development starts with the fertilization of an egg cell (ovum) by a sperm, sperm cell (spermat ...

, and immune responses) and adhesion of

epithelial cells Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...

, over-expressed in some cancers #Proline rich gla protein 1
PRRG1
or PRGP1) #Proline rich gla protein 2
PRRG2
or PRGP2) #Transmembrane γ-carboxy glutamyl protein 3
PRRG3
or TMG3, PRGP3) #Transmembrane γ-carboxy glutamyl protein 4
PRRG4
or TMG4, PRGP4)

References

Protein domains Peripheral membrane proteins {{membrane-protein-stub