• membrane cofactor protein, MCP

MAJOR LINKS FOR CD46  

• NCBI LocusLink Record: 4179
• Mendelian Inheritance in Man (OMIM): 120920
• SwissProt annotated protein record: P15529

• Cofactor for Factor I proteolytic cleavage of C3b and C4b

CELLULAR FUNCTION OF CD46  

• Sets a protective barrier threshold against inappropriate complement activation and deposition on plasma membranes, especially by the alternative pathway of complement activation, 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 coexpress multiple isoforms, no functions have been attributed to isoform coexpression
• Has been implicated as a ligand or protective molecule in fertilization:
• Acrosomal CD46 is exposed on the sperm head at sperm capacitation
• Crosslinking CD46 downregulates IL-12 production, via unknown mechanisms

DISEASE RELEVANCE OF CD46 AND FUNCTION OF CD46 IN INTACT ANIMAL  

• 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 sequelae of measles infections
• Transgenic expression in mice has potential as a model for measles infection
• Transgenic expression has potential for xenotransplantation: there is 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

• Families in which CD46 is a member
  • CD46-->regulators of complement activation gene

MOLECULAR STRUCTURE OF CD46  

• Single chain type I transmembrane molecule
• Four common (C1, C2, BC1, BC2) & other isoforms by alternate exon splicing plus glycosylation:

     ~56 kDa: "C1" 328 aa; "C2" 335 aa
     ~66 kDa: "BC1" 343 aa; "BC2" 350 aa
     ~76 kDa: "ABC1" 358 aa; "ABC2" 365 aa  

• Four 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 & regulatory activity
• The SCR1 module and sequences distal of SCR4 are not essential for complement regulatory function
• Heavily glycosylated membrane-proximal extracellular sequence
• Alternate (short) cytoplasmic sequences: "1" and "2" by splicing exon 13

MOLECULAR MASS OF CD46  

POST-TRANSCRIPTIONAL MODIFICATION OF CD46  

• Variable splicing predominantly of exons 7,8,9 and 13 yield the isoforms

POST-TRANSLATIONAL MODIFICATION OF CD46  

• Three N-linked glycosylation sites in SCR's 1, 2 & 4 (residues 83, 114, 273)
• The N-glycan on SCR2 is essential for measles virus binding
• Extensive serine/threonine glycosylation adjacent to the SCR modules; cell specific glycosylation may sort the sperm isoform to the acrosomal membrane
• Likely constitutive cytoplasmic site phosphorylation: no conclusive studies yet
• Trypsin resistant

SUBSTRATES FOR CD46   - No information

ENZYMES WHICH MODIFY CD46   - No information

LIGANDS FOR CD46 AND MOLECULES ASSOCIATED WITH CD46  

• Strongly expressed on salivary gland ducts and kidney ducts, moderately on lymphocytes and endothelium, weakly on interstitial tissues and muscle cells
• Often increased on tumor cells
• Not expressed on erythrocytes
• Relative proportions of the two major sized, coexpressed, isoforms are genetically determined on PBL as a Mendelian trait
• On cells other than PBL, relative levels of coexpressed isoforms are under tissue specific control
• Sperm form (within the acrosome) is probably from different exon splicing and glycosylation

• 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, 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 (eg., 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

SELECTION OF OTHER CD46-SPECIFIC REFERENCE MAB  

REVIEWS

1. Gerlier D,Varior-Krishnan G,Devaux P CD46-mediated measles virus entry: a first key to host-range specificity. Trends Microbiol 1995 3:338 PubMed

2. Liszewski MK,Farries TC,Lublin DM,Rooney IA,Atkinson JP Control of the complement system. Adv Immunol 1996 61:201 PubMed

3. Liszewski MK,Post TW,Atkinson JP Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster. Annu Rev Immunol 1991 9:431 PubMed

4. Vanderpuye OA,Labarrere CA,McIntyre JA The complement system in human reproduction. Am J Reprod Immunol 1992 27:145 PubMed

PRIMARY CITATIONS

5. Cho SW,Oglesby TJ,Hsi BL,Adams EM,Atkinson JP Characterization of three monoclonal antibodies to membrane co-factor protein (MCP) of the complement system and quantification of MCP by radioassay. Clin Exp Immunol 1991 83:257 PubMed

6. Hsi BL,Yeh CJ,Fenichel P,Samson M,Grivaux C Monoclonal antibody GB24 recognizes a trophoblast-lymphocyte cross- reactive antigen. Am J Reprod Immunol Microbiol 1988 18:21 * PubMed

7. Iwata K,Seya T,Yanagi Y,Pesando JM,Johnson PM,Okabe M,Ueda S,Ariga H,Nagasawa S Diversity of sites for measles virus binding and for inactivation of complement C3b and C4b on membrane cofactor protein CD46. J Biol Chem 1995 270:15148 PubMed

8. Johnstone RW,Russell SM,Loveland BE,McKenzie IF Polymorphic expression of CD46 protein isoforms due to tissue-specific RNA splicing. Mol Immunol 1993 30:1231 PubMed

9. Karp CL,Wysocka M,Wahl LM,Ahearn JM,Cuomo PJ,Sherry B,Trinchieri G,Griffin DE Mechanism of suppression of cell-mediated immunity by measles virus. Science 1996 273:228 PubMed

10. Kitamura M,Namiki M,Matsumiya K,Tanaka K,Matsumoto M,Hara T,Kiyohara H,Okabe M,Okuyama A,Seya T Membrane cofactor protein (CD46) in seminal plasma is a prostasome- bound form with complement regulatory activity and measles virus neutralizing activity. Immunology 1995 84:626 PubMed

11. Liszewski MK,Tedja I,Atkinson JP Membrane cofactor protein (CD46) of complement. Processing differences related to alternatively spliced cytoplasmic domains. J Biol Chem 1994 269:10776 PubMed

12. Lublin DM,Liszewski MK,Post TW,Arce MA,Le Beau MM,Rebentisch MB,Lemons LS,Seya T,Atkinson JP Molecular cloning and chromosomal localization of human membrane cofactor protein (MCP). Evidence for inclusion in the multigene family of complement-regulatory proteins. J Exp Med 1988 168:181 PubMed

13. Milland J,Christiansen D,Thorley BR,McKenzie IF,Loveland BE Translation is enhanced after silent nucleotide substitutions in A+T- rich sequences of the coding region of CD46 cDNA. Eur J Biochem 1996 238:221 PubMed

14. Naniche D,Varior-Krishnan G,Cervoni F,Wild TF,Rossi B,Rabourdin-Combe C,Gerlier D Human membrane cofactor protein (CD46) acts as a cellular receptor for measles virus. J Virol 1993 67:6025 PubMed

15. Niehans GA,Cherwitz DL,Staley NA,Knapp DJ,Dalmasso AP Human carcinomas variably express the complement inhibitory proteins CD46 (membrane cofactor protein), CD55 (decay-accelerating factor), and CD59 (protectin). Am J Pathol 1996 149:129 PubMed

16. Okabe M,Nagira M,Kawai Y,Matzno S,Mimura T,Mayumi T A human sperm antigen possibly involved in binding and/or fusion with Fertil Steril 1990 54:1121 PubMed

17. Okada N,Liszewski MK,Atkinson JP,Caparon M Membrane cofactor protein (CD46) is a keratinocyte receptor for the M protein of the group A streptococcus. Proc Natl Acad Sci U S A 1995 92:2489 PubMed

18. Pesando JM,Hoffman P,Abed M Antibody-induced antigenic modulation is antigen dependent: characterization of 22 proteins on a malignant human B cell line. J Immunol 1986 137:3689 * PubMed

19. Post TW,Liszewski MK,Adams EM,Tedja I,Miller EA,Atkinson JP Membrane cofactor protein of the complement system: alternative splicing of serine/threonine/proline-rich exons and cytoplasmic tails produces multiple isoforms that correlate with protein phenotype. J Exp Med 1991 174:93 PubMed

20. Purcell DF,McKenzie IF,Lublin DM,Johnson PM,Atkinson JP,Oglesby TJ,Deacon NJ The human cell-surface glycoproteins HuLy-m5, membrane co-factor protein (MCP) of the complement system, and trophoblast leucocyte- common (TLX) antigen, are CD46. Immunology 1990 70:155 PubMed

21. Russell SM,Sparrow RL,McKenzie IF,Purcell DF Tissue-specific and allelic expression of the complement regulator CD46 is controlled by alternative splicing. Eur J Immunol 1992 22:1513 PubMed

22. Seya T,Hara T,Matsumoto M,Akedo H Quantitative analysis of membrane cofactor protein (MCP) of complement. High expression of MCP on human leukemia cell lines, which is down- regulated during cell differentiation. J Immunol 1990 145:238 * PubMed

23. Seya T,Turner JR,Atkinson JP Purification and characterization of a membrane protein (gp45-70) that is a cofactor for cleavage of C3b and C4b. J Exp Med 1986 163:837 PubMed

24. Sparrow RL,McKenzie IF Hu Ly-m5: a unique antigen physically associated with HLA molecules. Hum Immunol 1983 7:1 PubMed

25. Stern PL,Beresford N,Thompson S,Johnson PM,Webb PD,Hole N Characterization of the human trophoblast-leukocyte antigenic molecules defined by a monoclonal antibody. J Immunol 1986 137:1604 * PubMed

26. Thorley BR,Milland J,Christiansen D,Lanteri MB,McInnes B,Moeller I,Rivailler P,Horvat B,Rabourdin-Combe C,Gerlier D,McKenzie IF,Loveland BE Transgenic expression of a CD46 (membrane cofactor protein) minigene: studies of xenotransplantation and measles virus infection. Eur J Immunol 1997 27:726 PubMed

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Portions copyright by Garland Press and by the International Workshops on Human Leukocyte Differentiation Antigens; used with permission

Modified 10/14/99   mpr@mail.nih.gov