CD46 complement regulatory protein also known as CD46 (

cluster of differentiation The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...

46) and Membrane Cofactor Protein is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

which in humans is encoded by the ''CD46''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. CD46 is an inhibitory complement receptor.

Gene

This gene is found in a cluster on

chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non- sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which ...

q32 with other genes encoding structural components of the complement system. At least fourteen different transcript variants encoding fourteen different isoforms have been found for this gene.

Function

The protein encoded by this gene is a type I membrane protein and is a regulatory part of the

complement system The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and ...

. The encoded protein has cofactor activity for inactivation (through cleavage) of complement components

C3b C3b is the larger of two elements formed by the cleavage of complement component 3, and is considered an important part of the innate immune system. C3b is potent in opsonization: tagging pathogens, immune complexes (antigen-antibody), and apoptot ...

and C4b by serum factor I, which protects the host cell from damage by complement. The protein encoded by this gene may be involved in the fusion of the

spermatozoa A spermatozoon (; also spelled spermatozoön; ; ) is a motile sperm cell, or moving form of the haploid cell that is the male gamete. A spermatozoon joins an ovum to form a zygote. (A zygote is a single cell, with a complete set of chromos ...

with the

oocyte An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female ...

during fertilization.

Clinical significance

The encoded protein can act as a receptor for the Edmonston strain of

measles virus ''Measles morbillivirus'' (MeV), also called measles virus (MV), is a single-stranded, negative-sense, enveloped, non-segmented RNA virus of the genus '' Morbillivirus'' within the family '' Paramyxoviridae''. It is the cause of measles. Human ...

, ''

human herpesvirus-6 Human herpesvirus 6 (HHV-6) is the common collective name for '' human betaherpesvirus 6A'' (HHV-6A) and '' human betaherpesvirus 6B'' (HHV-6B). These closely related viruses are two of the nine known herpesviruses that have humans as their prim ...

'' (HHV-6), group B adenoviruses, and type IV pili of pathogenic ''

Neisseria ''Neisseria'' is a large genus of bacteria that colonize the mucosal surfaces of many animals. Of the 11 species that colonize humans, only two are pathogens, '' N. meningitidis'' and ''N. gonorrhoeae''. ''Neisseria'' species are Gram-negativ ...

''. The extracellular region of CD46 contains four short consensus repeats (SCR) of about 60 amino acids that fold into a compact

beta-barrel In protein structures, a beta barrel is a beta sheet composed of tandem repeats that twists and coils to form a closed toroidal structure in which the first strand is bonded to the last strand (hydrogen bond). Beta-strands in many beta-barrels are ...

domain surrounded by flexible loops. As has been demonstrated for CD46 with other ligands, the CD46 protein structure is believed to linearize upon binding HHV-6. While their precise interaction has not yet been determined, the second and third SCR domains have been demonstrated to be required for HHV-6 receptor binding and cellular entry. The heterotetramer gH/gL/gQ1/gQ2 complex of HHV-6 has been identified as a CD46 ligand. Established

medulloblastoma Medulloblastoma is a common type of primary brain cancer in children. It originates in the part of the brain that is towards the back and the bottom, on the floor of the skull, in the cerebellum, or posterior fossa. The brain is divided into two ...

(a malignant brain tumor common in childhood) specimens express CD46, and that medulloblastoma specimens removed from patients had a high level of CD46 expression. Therefore, a vaccine made of the Edmonston strain of measles virus could treat the medulloblastoma. Such a vaccine has already been tested in a number of trials involving other tumor types which have a high expression of CD46, including one type of adult brain tumor. Recently, CD46 has emerged as a promising target for the treatment of both adenocarcinoma and neuroendocrine types of metastatic castration-resistant prostate cancer (mCRPC). YS5, a human full-length IgG1 with high specificity for CD46, was identified to have high binding affinity for prostate cancer tissue. YS5 has been developed into an antibody-drug conjugate, FOR46, which is currently in a phase I clinical trial (NCT03575819) for the treatment of mCRPC. Since then, a companion molecular imaging agent for CD46-targeted therapy has been developed.

Interactions

CD46 has been shown to

interact Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...

with CD9,

CD151 CD151 molecule (Raph blood group), also known as CD151 (Cluster of Differentiation 151), is a human gene. Function The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of ...

and

CD29 Integrin beta-1 (ITGB1), also known as CD29, is a cell surface receptor that in humans is encoded by the ''ITGB1'' gene. This integrin associates with integrin alpha 1 and integrin alpha 2 to form integrin complexes which function as collagen r ...

References

External links

GeneReviews/NCBI/NIH/UW entry on Atypical Hemolytic-Uremic Syndrome

OMIM entries on Atypical Hemolytic-Uremic Syndrome
* * * {{Complement system Clusters of differentiation