CD26 EC3.4.14.5, Tp103, DPP 4(dipeptidylpeptidase IV ectoenzyme), ADP (adenosine deaminase-binding protein)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Lineage Restricted Molecule
Type 2 glycoprotein
Prostate
Nonhematopoietic Cell
Leukocyte
T Cell
Thymocyte
Epithelial Cell
NK Cell
Macrophage
B Cell
Kidney
Spleen
Monocyte
Small intestine
Bile duct
Epithelium
110 / 110
120 / 120

Expression
CD26 is expressed on mature thymocytes, activated T and B cells, NK cells, macrophages and monocytes.  It is also expressed on renal proximal tubular epithelial cells, small intestinal epithelium, kidney, bile duct, biliary canaliculae, splenic sinus lining cells and in the prostate gland.  CD26 is expressed primarily on mature thymocytes in the medulla.  Expression is weak on mature T cells and is restricted to memory T cells.  CD26 is upregulated on  activated memory T cells.

Structure
MOLECULAR FAMILY NAME FOR CD26: Belongs to the poly-oligopeptidase family.

CD26 is a single-pass type-2 homodimeric 766 aa glycoprotein.  It contains an extracellular domain which contains 3 regions, a membrane-proximal glycosylated region starting with a 20 aa flexible stalk region with 9 N-glycosylation sites, a cysteine-rich region and a 260 aa C-terminal region contain dipeptidyl peptidase IV activity, a 22 aa hydrophobic transmembrane domain and a 6 aa cytoplasmic domain.  The C-terminal region contains the putative catalytic site, consisting of Ser630 (Gly-Trp-Ser-Tyr-Gly motif with 628 aa-632 aa), Asp708 and His740, in the reverse order of the serine protease family.  These form the catalytic triad located in the α/β hydrolase fold in the C-terminus.  The remaining N-terminal amino acids form an eight-bladed βB propeller.  The hydrolase and propeller domains are required for dimerization.  CD26 is expressed as a noncovalently linked homodimer in the membrane or is released as a truncated soluble form.  CD26 is associated with human immunodeficiency virus (HIV) disease progression, which is a feature of many other T cell molecules.  There is some correlation between CD26 expression and HIV entry, replication and cytopathicity.  In addition, CD26 is downregulated as the disease progresses.  However, CD26 is clearly not a coreceptor for HIV, as was originally reported.  Dipeptidyl peptidase IV EC 3.4.14.5 activity has been measured in serum, but this does not appear to be the result of CD26 cleavage from the cell surface.  Instead, a novel 175 kDa T cell antigen DPPT-L, related to CD26, is thought to be responsible.

MOLECULAR MASS
Cell Type Unreduced Reduced
Activated T cells  110 kDa 110, 120 kDa

POST-TRANSCRIPTIONAL MODIFICATION

CD26 has no alternate splicing, all 26 exons are translated.  CD26 has 9 potential glycosylation sites and different glycosylated forms which are detected by immunoprecipitation with different CD26 mAbs.

POST-TRANSLATIONAL MODIFICATION

CD26 has 9 potential glycosylation sites and different glycosylated forms which are detected by immunoprecipitation with different CD26 mAbs.



Ligands
CD26 binds fibroblast activation protein (FAP) and the Tat protein of HIV.  CD26 associates non-covalently with adenosine deaminase (ADA), the deficiency of which results in severe combined immunodeficiency (SCID) in humans.  This interaction is mediated by the extracellular region of CD26 and is not dependent on catalytic activity.  CD26 co-immunoprecipitates and co-modulates with CD45 on T cells.  A ligand for CD26 is the extracellular matrix protein collagen.  This interaction does not require CD26 catalytic activity and mAb blocking studies indicate that the binding site is within residues 236-491.

LIGANDS AND MOLECULES ASSOCIATED WITH CD26
Molecule Comment
Adensosine-deaminase
Collagen
CD45




Function
CD26 is reported to be a regulatory of growth and differentiation and also as a differentiation antigen for endometrial surface and glandular epithelium.  CD26 also functions as a co-stimulatory molecule in T cell activation.  CD26 is proposed to perform 3 distinct functions, as a membrane bound protease, a T cell co-stimulatory molecule and a cell adhesion molecule.  CD26 has a unique specificity amongst cell surface serine proteases.  Dipeptides are cleaved from the N-terminus of polypeptides if proline is at the penultimate position.  This enzymatic activity is responsible for the intestinal digestion and renal transport of proline-containing polypeptides.  Indeed, the Fischer 344 rat strain lacks functional CD26, resulting in impaired renal absorption of proline-containing peptides.  CD26 also functions as a T cell co-stimulatory molecule.  Expression of the TCR complex is required for CD26 signaling, in which the TCR z chain is necessary but not sufficient.  The mechanism for CD26 signaling is not known, but may be related to the association of CD26 with CD45 and ADA.  Independent of its enzymatic activity, CD26 plays a role in lymphocyte proliferation probably via binding of ADA and possibly via its association with CD45.  In particular, ADA binding to CD26 on T cells is proposed to reduce the local concentration of adenosine, a nucleoside which inhibits T cell proliferation.  The cell adhesion role of CD26, in binding to the extracellular matrix via collagen, does not depend on catalytic activity and it is not clear whether this activity is required for CD26 signaling.  CD26 can bind fibroblast activation protein but the effects of this interaction have yet to be elucidated. 

BIOCHEMICAL ACTIVITY

Exopeptidase cleaves off  the N-terminal X-proline or X-alanine dipeptides from polypeptides, a dipeptidyl peptidase IV activity.  Independent of its enzmatic activity, CD26 plays a role in lymphocyte proliferation probably via binding of adenosine deaminase (APA) and possibly via its association with CD45.

DISEASE RELEVANCE AND FUNCTION OF CD26 IN INTACT ANIMAL

CD26 is an associated marker of autoimmune diseases, adenosine deaminase-deficiency and HIV pathogenesis.   Immunosuppression during HIV infection may be mediated by inactivation of CD26 by the binding of the HIV protein Tat to the adenosine deaminase (ADA) binding site.  CD26 binds collagen in the extracellular matrix with possible role in tissue restructing in tumors and liver disease.  Human studies support a role for CD26 as a potential therapeutic agent in control of type-2 diabetes.  Knockout mice demonstrate a role for CD26 in regulating blood glucose levels probably by inactivating incretins such as glucagon-like peptide-1 (GLP-1) which are responsible for about 50% of nutrient-induced insulin secretion and have other roles in glucose homeostasis.

Comments

MOLECULAR INTERACTIONS-
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD26

Molecule Comment
SP-1 Transcription regulation
AP2 Transcription regulation
c-myb Transcription regulation
c-myc Transcription regulation
Butyrate-responsive element (BRE) Transcription regulation
HNF-1 Transcription regulation
NF-kB Transcription regulation

SUBSTRATES FOR CD26

Oligopeptides containing proline or alanine are at the penultimate position. No natural substrates are identified yet.

ENZYMES WHICH MODIFY CD26: No information.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 1803P27487
MouseS23752P28843X58384
RatA33315P14740J04591
Antibodies
CACT114A   View Reactivity
CC69   View Reactivity
CLB-22C3   View Reactivity
M-A261   View Reactivity

Revised June 25, 2008


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