Membrane cofactor protein

Gene

CD46 is found in a cluster on chromosome 1q32 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 encoded protein has cofactor activity for inactivation (through cleavage) of complement components C3b 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 with the oocyte during fertilization.

Clinical significance

Measles infection

The encoded protein can act as a receptor for the Edmonston strain of measles virus, human herpesvirus-6 (HHV-6), group B adenoviruses, and type IV pili of pathogenic Neisseria.

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

Medulloblastoma

Established medulloblastoma (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.

Prostate cancer

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.

Inflammatory diseases

CD46 deficiency contributes to inflammation disorders.

Interactions

CD46 has been shown to interact with CD9, CD151 and CD29.

References

References

1. (May 1994). "Inhibition of human spermatozoon-oocyte interaction in vitro by monoclonal antibodies to CD46 (membrane cofactor protein)". Human Reproduction.
2. (1991). "Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster". Annual Review of Immunology.
3. "Entrez Gene: CD46 CD46 molecule, complement regulatory protein".
4. (September 2004). "CD46: expanding beyond complement regulation". Trends in Immunology.
5. (November 2005). "Emerging roles and new functions of CD46". Springer Seminars in Immunopathology.
6. (September 1994). "CD46, a primate-specific receptor for measles virus". Trends in Microbiology.
7. (November 2003). "CD46 is a cellular receptor for group B adenoviruses". Nature Medicine.
8. (May 2004). "Four viruses, two bacteria, and one receptor: membrane cofactor protein (CD46) as pathogens' magnet". Journal of Virology.
9. (August 2011). "The molecular biology of human herpesvirus-6 latency and telomere integration". Microbes and Infection.
10. (July 2009). "Recent topics related to human herpesvirus 6 cell tropism". Cellular Microbiology.
11. (October 2010). "Treatment of medulloblastoma with a modified measles virus". Neuro-Oncology.
12. (September 2018). "Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer". JCI Insight.
13. (December 2006). "Identification of clinically significant tumor antigens by selecting phage antibody library on tumor cells in situ using laser capture microdissection". Molecular & Cellular Proteomics.
14. (March 2021). "Molecular Imaging of Prostate Cancer Targeting CD46 Using ImmunoPET". Clinical Cancer Research.
15. (October 2021). "Membrane cofactor protein (MCP; CD46): deficiency states and pathogen connections". Current Opinion in Immunology.
16. (March 2000). "CD46 (membrane cofactor protein) associates with multiple beta1 integrins and tetraspans". European Journal of Immunology.