CD224 GGT1 (γ glutamyltransferase 1), GGT, γ-glutamyltranspeptidase
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 2 glycoprotein
T Cell
Stem Cell
Lymphocyte
Monocyte
Granulocyte
Endothelial Cell
Kidney
Liver
Pancreas
Stomach
Small intestine
Placenta
Lung
B Cell
Macrophage
Epithelial Cell
Endothelium
Peripheral blood
Hepatocyte
21 / 21
100 / 100

Expression
CD224 is expressed on lymphocytes, monocytes, granulocytes, endothelial and stem cells.    CD224 is strongly expressed in tissues of renal tubular cells, hepatocytes and by cells in the pancreas, epididymis and seminal vesicles, vascular endothelium, alveolar epithelial and peripheral blood macrophages, a small subset of B cells and a specific subset of T cells.  There is little or no expression on resting CD45RA+ T cells.  Expression is upregulated with T cell activation and remains elevated on CD45R0+ T cells.  Expression is also detected in fetal and adult kidney, liver, adult pancreas, stomach, intestine, placenta, and lung.

Structure
MOLECULAR FAMILY NAME: Belongs to the thronine peptidase family.

CD224 is a single-pass type-2 glycoprotein.  It contains an extracellular domain, a transmembrane domain and a cytoplasmic domain.   Human g-glutamyltransferase (GGT) catalyzes the transfer of the glutamyl moiety of glutathione to a variety of aa and dipeptide receptors.  CD224 is an ectoenzyme which contains a 380 aa heavy chain and an 189 aa light chain which are translated from a single mRNA.  The protein is then proteolytically cleaved into two subunits and assembled into the active enzyme and is present in tissues involved in absorption and secretion.  The heavy chain contains a short transmembrane segment adjacent to the amino-terminus containing a positively charged amino acids and contains 5-6 N-linked glycosylation sites.  The 189 aa light chain is non-covalently associated with the heavy peptide and contains 2 N-linked glycosylation sites. The catalytic domain is located on the light chain.  Soluble CD224  is detected in blood and is the result of proteolytic cleavage and is assembled into an active enzyme.  This enzyme is a member of the GGT protein family, of which many members have not yet been fully characterized.  The enzyme is presnt in the lung surfant but as this form retains its signal anchor transmembrane, it is not a product of proteolytic cleavage.  This gene encodes several transcript variants. Studies suggest that many transcripts of this gene family may be non-functional or represent pseudogenes.  The functional transcripts which have been fully characterized have been grouped and classified as type GGT.  Complex splicing events may take place in a tissue-specific manner, resulting in marked dissimilarity in the 5'UTRs.  Several 5'UTR transcript variants of the type 1 gene have been identified in different tissues and cancer cells.  The CD224 splice variant 1 includes a distinct 5'UTR and encodes the pancreatic form of the protein GGT1.  Transcript variants 1, 2, and 3 specify the same protein, but variant 1 includes 5 exons in the 5'UTR with a length of 358 bps.  Splice variant 2 includes a distinct 5'UTR and encodes the placenta form of the protein GGT1 precursor.  Transcript variants 1, 2, and 3 specify the same protein, but variant 2 includes 6 exons in the 5'UTR with a length of 669 bps.  Splice variant 3 includes a distinct 5'UTR and encodes the heptoma of the protein GGT 1. Transcript variants 1, 2, and 3 specify the same protein, but variant 3 includes 7 exons in the 5'UTR, 5 of which are also found in variant 1, with a length of 487 bps.

MOLECULAR MASS
Cell Type Unreduced Reduced
Lymphocytes 100 kDa 55-60 kDa heavy subunit & 21-30 kDa light subunit

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 3 different isoforms.  CD224 has multiple potential N-glycosylation sites on both the heavy and light chains resulting in multiple isoforms characterized by differential glycosylation.  A sugar chain structure has been analyzed in the rat renal enzyme.  A cancer-associated alteration of the sugar chain has also been described.

POST-TRANSLATIONAL MODIFICATION

The precursor protein is cleaved and the heavy and light segments are non-covalently assembled to form an active enzyme.  CD224 is heavily and heterogeneously glycosylated and has 5-7 potential N-glycosylation sites on the heavy chain and 1-2 sites on the light chain.


Ligands
LIGANDS AND MOLECULES ASSOCIATED WITH CD224
Molecule Comment
CD19 Non-covalently associated on B lymphoblastoid cells
CD21 Non-covalently associated on B lymphoblastoid cells
CD37 CD37 associates with CD224
CD53 CD53 associates with CD224
CD81 Non-covalently associated on B lymphoblastoid cells
CD82 Non-covalently associated on B lymphoblastoid cells and T lymphoblasts


Function
CD224 maintains intracellular glutathione (GSH) concentrations and consequently a state of oxidative homeostasis with cellular microenviroments.  CD224 is an integral part of the γ-glutamyl cycle and is essential for maintaining the homeostatic balance of the cellular redox.  It binds the γ-glutamyl  portion of GSH, cleaves glutamate from GSH or transfers the γ-glutamyl residue to another amino acid or dipeptide.  GSH must first be broken down into its individual aa, which are then transported into the cell and used de novo GSH synthesis.  CD224 is the first enzyme involved in the breakdown of GSH by this pathway and binds the g-glutamyl portion of the GSH tri-peptide and either hydrolyzes the g-glutamyl bond releasing glutamate, or transfers the g-glutamyl group to another aa or depeptide.  The remaining cysteinyl-glycine can be further broken down by a membrane bound dipeptidase for uptake by the cell.  The remaining cysteinyl-glycine can be further broken down by a membrane bound dipeptidase for uptake by the cell.  Mammalian cells lack the ability to transport GSH into the cell from extracellular spaces.  CD224 is involved in cellular detoxification and in leukotriene biosynthesis and inhibits apoptosis.  CD224 can convert leukotriene C4 to leukotriene D4 and has been shown to convert the nitric acid donor, GSNO to the unsable form s-nitrocycteinylglycine, thereby providing nitric oxide to the cell.  CD224 associates with CD37 and CD53 and has been found to noncovalently associate with CD19, CD21, CD81 and CD82 in a B lymphoblastoid cell line.

BIOCHEMICAL ACTIVITY

CD224 is a transpeptidase located in the plasma membrane.

DISEASE RELEVANCE AND FUNCTION OF CD224 IN INTACT ANIMAL.

CD224 autosomal recessive defects in humans with glutathionuria and in at least 1 case of mild mental retardation have been described.  The importance of CD224 in a whole animal model was demonstrated by creation of a CD224 deficient mouse.  Characteristics of the deficient knockout mice includes elevated levels of GSH and GSH conjugates in plasma and urine with decreased concentrations in tissues.  These mice are growth retarded, sexually immature, develop cataracts and demonstrate significant mortality beginning between 8-12 weeks old.  The glutathionuria results in the whole body depletion of cysteine.  The effects of the CD224 deficiency can be partially reversed by feeding the CD224 deficient mice with N-acetyl cysteine, which provides an abundant source of the rate limiting aa for GSH synthesis and cysteine.  CD224 activity is increased in liver disease.


Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD224: No information.

SUBSTRATES
Substrate Comment
Glutathione
Glutathione S-conjugates CD224 is involved in excretion of glutathione S-conjugates
Leukotriene C4 CD224 is involved in conversion of leukotriene C4 to leukotriene D4
S-nitrosoglutathione (GSNO) CD224 has been shown to convert the relatively stable nitric oxide donor, GSNO to the unstable S-nitrosocysteinylglycine, thus delivering nitric oxide to CD224-expressing cells


ENZYMES WHICH MODIFY CD224: No information.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 2678P19440
Antibodies

Revised June 25, 2008


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