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 polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of s ...
that contains post-translational modifications of many glutamate residues by
vitamin K
Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...
-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 carboxylatio ...
to form
γ-carboxyglutamate
Carboxyglutamic acid (or the conjugate base, carboxyglutamate), is an uncommon amino acid introduced into proteins by a post-translational carboxylation of glutamic acid residues. This modification is found, for example, in clotting factors and ...
(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 R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...
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) is a Protein in humans which is encoded 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 glycoprotein. Protein Z functi ...
. 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 gl ...
, the calcification-inhibiting
matrix Gla protein
Matrix Gla protein (MGP) is member of a family of vitamin K2 dependent, Gla-containing proteins. MGP has a high affinity binding to calcium ions, similar to other Gla-containing proteins. The protein acts as an inhibitor of vascular mineralizat ...
(MGP), the
cell growth
Cell growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis (production of biomolecules or anabolism) is greater than ...
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 ar ...
,
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 and alpha-V/beta-5 integrins to support adhesion and migration of epithel ...
(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 potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...
, Gla region
Human proteins containing this domain
#
Thrombin
Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...
(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 blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...
#
Factor VII
Coagulation factor VII (, formerly known as proconvertin) is one of the proteins that causes blood to clot in the coagulation cascade, and in humans is coded for by the gene ''F7''. It is an enzyme of the serine protease class. Once bound to tis ...
(F7) – involved in coagulation
#
Factor IX
Factor IX (or Christmas factor) () is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes haemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas w ...
(F9) – involved in coagulation
#
Factor X
Factor X, also known by the eponym Stuart–Prower factor, is an enzyme () of the coagulation cascade. It is a serine endopeptidase (protease group S1, PA clan). Factor X is synthesized in the liver and requires vitamin K for its synthesis.
Fac ...
(F10) – involved in coagulation
#
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIX, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and apoptosis, cell death and ...
(PROC) – roles in regulating
anticoagulation
Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where the ...
,
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
,
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 dis ...
, 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 huma ...
(PROS1) – involved in coagulation
#
Protein Z
Protein Z (PZ or PROZ) is a Protein in humans which is encoded 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 glycoprotein. Protein Z functi ...
(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 gl ...
(BGLAP) – involved in
bone mineralization
Biomineralization, also written biomineralisation, is the process by which living organisms produce minerals, often to harden or stiffen existing tissues. Such tissues are called mineralized tissues. It is an extremely widespread phenomenon; ...
.
#
Matrix gla protein
Matrix Gla protein (MGP) is member of a family of vitamin K2 dependent, Gla-containing proteins. MGP has a high affinity binding to calcium ions, similar to other Gla-containing proteins. The protein acts as an inhibitor of vascular mineralizat ...
(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 Mat ...
of soft tissue and plays a role in bone organization
#
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 ar ...
– 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 Alpha-1-microglobulin/bikunin precursor, AMBP or SPINT2 ...
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 and alpha-V/beta-5 integrins to support adhesion and migration of epithel ...
– a factor necessary for cell migration (
embryonic development
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
, and
immune responses
An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...
) and adhesion of
epithelial cells
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
, over-expressed in some cancers
#Proline rich gla protein 1
PRRG1or PRGP1)
#Proline rich gla protein 2
PRRG2or PRGP2)
#Transmembrane γ-carboxy glutamyl protein 3
PRRG3or TMG3, PRGP3)
#Transmembrane γ-carboxy glutamyl protein 4
PRRG4or TMG4, PRGP4)
References
Protein domains
Peripheral membrane proteins
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