CD40 Bp50, TNF receptor 5
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
B Cell
Endothelial Cell
Leukemia cell
Lymphoid Cell
Follicular Cell
Dendritic Cell
Plasma Cell
Epithelial Cell
Macrophage
Fibroblast
Keratinocyte
Hematopoietic Cell
Monocyte
Carcinoma Cell
48 / 48
85 / 85

Expression
CD40 is expressed on the surface of all mature B cells including pro-B cells through to plasma cells, most B cell malignancies and some early B cell acute lymphocytic leukemias. It is also present on basal epithelial cells, epithelial cell carcinomas, activated monocytes, macrophages, follicular dendritic cells, endothelial cells, fibroblasts, keratinocytes, and interdigitating cells.  CD34+ hematopoietic cell progenitors are also positive.


Structure
MOLECULAR FAMILY NAME: Belongs to the tumor necrosis factor receptor family.

CD40 is a single-pass type-1 glycoprotein.  It contains an 193 aa extracellular domain which contains 4 cysteine-rich repeats, a 22 aa hydrophobic transmembrane domain and a 42 aa cytoplasmic domain containing 2 distinct functional domains.  The overall polypeptide portion is about 28 kDa, indicating that about 20 kDa of the polypeptide may consist of carbohydrate.

MOLECULAR MASS
Cell type Unreduced Reduced Comment
B lymphocytes (85 kDa dimers) 48 kDa

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 2 different isoforms.

POST-TRANSLATIONAL MODIFICATION

CD40 is glycosylated.  There is a 48 kDa glycoprotein appearing as 39 kDa post-deglycosylation and phosphorylated on serine/threonine residues but there is no tyrosine phosphorylation.

Ligands
CD40 binds to CD154, a type 2 membrane protein of the TNF superfamily.  The cytoplasmic domain of CD40 binds to CRAF-1, a member of the TRAF, TNFR-associated proteins, family.  Binding is dependent on Thr 234 which is an essential residue for signal transduction via CD40.  A novel 23 kDa protein coprecipitates specifically for CD40.

LIGANDS AND MOLECULES ASSOCIATED WITH CD40
Molecule Comment
CD154 (CD40L) Inducible membrane of TNF-family of molecules on TH cells




Function
CD40 binds the ligand CD154 (CD40L) and has a role in B lymphocyte maturation.  CD40 has been found to be essential in mediating a broad variety of immune and inflammatory responses including T-cell dependent immunoglobulin class-switching, memory B cell development and germinal center formation.  AT-hook transcription factor AKNA is reported to coordinately regulate the expression of this receptor and its ligand, CD154, which may be important for homotypic cell interactions.  Adaptor protein CD120b (TNFR2) interacts with CD40 and serves as a mediator of signal transduction.  CD40 on B cells, is involved in growth, differentiation, and isotype-switching and is a potent rescue signal from apoptosis in germinal center B cells therefore influencing B-cell selection.  CD40 antibodies can deliver progression signals that augment the proliferation of activated B cells.  CD40 is involved in cognate T-B interaction and is central to T-cell dependent responses.  CD40 antibodies are costimulatory with competence signals including anti-IgM, CD20 antibodies and PMA, but are not costimulatory with IL-4 or low-molecular weight B-cell growth factor.  CD40 promotes cytokine production in macrophages and dendritic cells. CD40 upregulates adhesion molecules on dendritic cells and keratinocytes and stimulates growth arrest in epithelial cells.  CD154 binding to CD40 on B cells is required for secondary immune responses and the germinal center formation.  There is evidence for a role for the CD154-CD40 interaction in negative selection and peripheral tolerance. 

BIOCHEMICAL ACTIVITY: No information.

DISEASE RELEVANCE AND FUNCTION OF CD40 IN INTACT ANIMAL:

CD40 function is central to T cell dependent responses.  CD40 may influence survival of B cell lymphomas and may be an important target for the control of graft rejection and T cell antibody mediated autoimmune diseases.  The CD40 antibody can substitute for CD40 ligand in activates B cells.  CD40 and its ligand, CD154 (CD40L), is found to be necessary for amyloid-β-induced microglial activation, and thus is thought to be an eary event in Alzheimer disease pathogenesis.  CD40 is a potential therapeutic target in treatment of autoimmunity, allograft rejection and atherosclerosis.  Mutation in CD40 are associated with immune deficiency disorder, hyper-IgM syndrome, a autosomal recessive disorder, which is characterized by the lack of isotype switching in Ig production and the lack of germinal centers.  Knockout mice are more susceptible to parasite infection.

Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD40: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD40: No information.

ADDITIONAL INSIGHTS

There is an intriguing question of different epitopes displaying differential functions. Is there another ligand(s)? Signal transduction pathways engaged appear different at different stages of B cell differentiation. CD40 plays a central role in the regulation of cell-mediated immunity as well as antibody mediated immunity.

Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 958P25942
MouseA46476P27512M83312
Antibodies
5C3   View Reactivity
HB14   View Reactivity
MAB89   View Reactivity

Revised June 25, 2008


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