CD46 MCP (membrane co-factor protein)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Blood Cell, Peripheral
Platelet
Endothelial Cell
Fibroblast
Kidney
Tumor Cell
Brain
52 / 52
78 / 78

Expression
CD46 is expressed on all peripheral blood cells and platelets at variable levels but not on erythrocytes.  It is widely expressed on fibroblasts and white blood cells.  It is strongly expressed on blood-brain barrier, salivary gland ducts and kidney ducts, moderately on endothelial cells and lymphocytes.  CD46 is weak on and epithelial cells, weak on interstitial tissues and muscle cells, and tissues of the reproductive system, including fallopian tube, uterine endometrium, placenta and sperm.  CD46 is expressed on all nucleated cells but is not expressed on unfertilized oocytes but appears at the 6-8 cell stage embryo.  Expression is often increased on tumor cells.  Relative proportions of the 2 major sized co-expressed isoforms are genetically determined on PBL as a Mendelian trait.  On cells other than PBL with relative levels of co-expressed isoforms are under tissue specific control.  The sperm form within the acrosome is probably from different exon splicing and glycosylation.


Structure
MOLECULAR FAMILY NAME: Belongs to the regulators of complement activation gene cluster family.

CD46 is a single-pass type-1 glycoprotein.  It contains 4 common complement control protein (CCP) domains, C1, C2, BC1, BC2 and other isoforms by alternate exon splicing plus glycosylation are:
~56 kDa C1 238 aa C2 335 aa
~66 kDa BC1 343 aa BC2 350 aa
~76 kDa ABC1 358 aa ABC2 365 aa

CD46 contains 4 N-terminal short consensus repeat (SCR) modules, "Sushi" domains: 4 Cys in 1-3,2-4 linkage. SCR2,3,4 modules have the C3b/C4b binding and regulatory activity.  The SCR1 module and sequences distal of SCR4 are not essential for the complement regulatory function.  CD46 has a heavily glycosylated membrane-proximal extracellular sequence and an alternate short cytoplasmic sequences, "1" and "2" by splicing exon 13.  There are 6 CD46 isoforms determined from cDNA clones derived from the combination of 3 isoforms in the Ser/Thr/Pro rich (STP) region and 2 isoforms in the cytoplasmic domain.  The 3 variants in the STP region express both STP A and STP B exons, only STP B, or neither exon.  The 2 cytoplasmic domains, CY1 and CY2, are the consequence of the presence or absence of the exon 13. Thus the 6 isoforms are designated: a 358 aa ABC1, a 365 aa ABC2, a 343 aa BC1, a 350 aa BC2, a 238 aa C1 and a 335 aa C2.  A, B and C indicate the expression of the STP A, STP B and STP C exons, and 1 and 2 denote the cytoplasmic exons expressed.  However, the 2 isoforms ABC1 and ABC2 have not been observed in peripheral blood cells or cell lines.  Most cells of a given individual express the same ratio of the 4 remaining isoforms, although selective expression of certain isoforms has been noted in the brain, kidney and salivary gland.

MOLECULAR MASS
Cell Type Unreduced Reduced Comment
Lymphocytes 52-58 kDa 64-68 kDa
Tumor cells 52-58 kDa 64-68 kDa, 72-78 kDa
Placental trophoblasts 52-58 kDa 64-68 kDa, 72-78 kDa
Sperm 35-40 kDa

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 16 different isoforms.  Four main isoforms (C1, C2, BC1 and BC2) and two other isoforms (ABC1 and ABC2) occur due to variable splicing of predominantly of exons 7, 8, 9 and 13 and glycosylation.

POST-TRANSLATIONAL MODIFICATION

There are 3 N-linked glycosylation sites are in SRCs 1, 2 & 4, residues 83, 114, 273. The N-glycan on SCR2 is essential for measles virus binding.  Extensive serine/threonine glycosylation is adjacent to the SCR modules. Cell specific glycosylation may sort the sperm isoform to the acrosomal membrane.  There is a likely constitutive cytoplasmic site phosphorylation but there are no conclusive studies yet.  CD46 is trypsin resistant.

Ligands
CD46 binds the complement components C3b and Cb4 allowing degradation by Factor 1 and is a receptor for the measles virus and for Streptococcus pyogenes.  CD46 also associates with β1 integrins and tetraspanin molecules.

LIGANDS AND MOLECULES ASSOCIATED WITH CD46
Molecule Comment
Serum factor I protease CD46 is co-factor, binds SRC 2/3/4 modules
C3b Binds SCR 2/3/4 modules
C4b Binds SCR 2/3/4 modules
Measles virus hemagglutinin Receptor binding via SCR1, 2 modules
Streptococcus A surface protein Plasma factor H may be its principal receptor



Function
CD46 is a member of the regulator of complement activation (RCA) family of proteins.   CD46 inhibits complement activation by inhibition of C3 convertase formation.  It acts as a co-factor which binds to C3b and C4b, thereby permitting factor I, a serine protease of the complement system, to convert C3b and C4b into fragments that cannot support further complement activation and protecting host tissues from complement-mediated damage.  Of the variants that have different STP regions, the BC isoforms are found to be more efficient than the C isoforms in the regulation of C4b activity, although both sets of isoforms have similar regulatory activities on C3b.  CD46 regulates T cell inflammatory responses and contact hypersensitivity reaction with different effects depending on the cytoplasmic tail type 1 (Cyt-1) has been shown to be processed 4 times faster into its mature forms.  Cyt-1 engagement suppresses inflammation, whereas Cyt-2 prototes inflammation.  CD46 sets a protective barrier threshold against inappropriate complement activation and deposition on plasma membranes, especially by the alternative pathway of complement activation, and by limiting formation and function of the C3 convertases.  No distinct functions have been attributed to tissue-specific isoforms and the variable levels of expression.  Although all nucleated human cells co-express multiple isoforms, no functions have been attributed to isoform co-expression. CD46 has been implicated as a ligand or protective molecule in fertilization.  Acrosomal CD46 is exposed on the sperm head at sperm capacitation.  The complement regulatory proteins CD46, CD55 and CD59 are likely to be important in protecting the sperm and fetus from rejection by the maternal immune system.  Knockout mice demonstrate an increased rate of acrosomal reaction and a higher fertility rate compared with wild type mice, suggesting a regulatory role for CD46.  
Transgenic pigs are being produced which express human complement regulatory proteins in order to prevent complement-mediated hyperacute rejection - a major problem in xenotransplantation of pig organs to humans.  Crosslinking CD46 downregulates IL-12 production, via unknown mechanisms.  CD46 associates with β1 integrins ans tetraspanins.

BIOCHEMICAL ACTIVITY

CD46 is a co-factor for factor I proteolytic cleavage of C3b and C4b.

DISEASE RELEVANCE AND FUNCTION OF CD46 IN INTACT ANIMAL

CD46 acts as the receptor for the Edmonston strain measles virus. Herpes virus, S. pyogenes and type IV pili of pathogenic Neisseria sp.  No deficiencies or CD46 mutations on human tissues have been substantiated.  The effect of crosslinking CD46 on reduction of IL-12 production may be especially important in the immunosuppressive sequel of measles infections.  Transgenic expression in mice has the potential as a model for measles infection and for xenotransplantation.  There is a dispute about the relevance of species differences in complement proteins affecting their function.  Recombinant expression of single isoforms to high levels has been difficult to obtain.  CD46 may be involved in the fusion of the spermatozoa with the oocyte during fertilization.


Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD46: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD46: No information.

ADDITIONAL INSIGHTS

CD46 is an unusual member of the complement regulating family of proteins based on the multiple isoforms and the pattern of tissue-specific expression in quantity and isoform proportion, the lack of mutants / deficiencies and quirks in obtaining expression from cDNA, and genomic and minigene constructs after transfection and transgenesis.  The high efficiency regulation of the alternative pathway activation may have therapeutic implications.  The role of CD46 in fertilization remains controversial, although other mammalian homologs such as the Guinea pig may be testis-specific and point to an important adaptation or original function.  The reason(s) for alternative cytoplasmic C-termini, and potential signaling effects, remain unknown and investigations are only beginning.

Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 4179P15529
Antibodies
E4.3   View Reactivity
J4-48   View Reactivity
JM6C11   View Reactivity

Revised June 25, 2008


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