CD46

CD46 complement regulatory protein also known as CD46 (cluster of differentiation 46) and Membrane Cofactor Protein is a protein which in humans is encoded by the CD46 gene.[5] CD46 is an inhibitory complement receptor.[6]

CD46
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCD46, AHUS2, MCP, MIC10, TLX, TRA2.10, CD46 molecule
External IDsOMIM: 120920 MGI: 1203290 HomoloGene: 7832 GeneCards: CD46
Orthologs
SpeciesHumanMouse
Entrez

4179

17221

Ensembl

ENSG00000117335

ENSMUSG00000016493

UniProt

P15529

O88174

RefSeq (mRNA)

NM_010778

RefSeq (protein)

NP_034908

Location (UCSC)Chr 1: 207.75 – 207.8 MbChr 1: 194.72 – 194.77 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gene

This gene 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.[7]

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.[8]

The protein encoded by this gene may be involved in the fusion of the spermatozoa with the oocyte during fertilization.[9]

Clinical significance

Measles infection

The encoded protein can act as a receptor for the Edmonston strain of measles virus,[10] human herpesvirus-6 (HHV-6), group B adenoviruses,[11] and type IV pili of pathogenic Neisseria.[12]

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.[13] 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.[14]

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.[15]

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).[16][17] YS5, a human full-length IgG1 with high specificity for CD46, was identified to have high binding affinity for prostate cancer tissue.[16] 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.[18]

Inflammatory diseases

CD46 deficiency contributes to inflammation disorders.[19]

Interactions

CD46 has been shown to interact with CD9,[20] CD151[20] and CD29.[20]

References
  1. GRCh38: Ensembl release 89: ENSG00000117335 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000016493 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Taylor CT, Biljan MM, Kingsland CR, Johnson PM (May 1994). "Inhibition of human spermatozoon-oocyte interaction in vitro by monoclonal antibodies to CD46 (membrane cofactor protein)". Hum. Reprod. 9 (5): 907–11. doi:10.1093/oxfordjournals.humrep.a138615. PMID 7929741.
  6. Liszewski MK, Post TW, Atkinson JP (1991). "Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster". Annu. Rev. Immunol. 9 (1): 431–55. doi:10.1146/annurev.iy.09.040191.002243. PMID 1910685.
  7. "Entrez Gene: CD46 CD46 molecule, complement regulatory protein".
  8. Riley-Vargas RC, Gill DB, Kemper C, Liszewski MK, Atkinson JP (September 2004). "CD46: expanding beyond complement regulation". Trends Immunol. 25 (9): 496–503. doi:10.1016/j.it.2004.07.004. PMID 15324743.
  9. Liszewski MK, Kemper C, Price JD, Atkinson JP (November 2005). "Emerging roles and new functions of CD46". Springer Semin. Immunopathol. 27 (3): 345–58. doi:10.1007/s00281-005-0002-3. PMID 16200405. S2CID 28240864.
  10. Dörig RE, Marcil A, Richardson CD (September 1994). "CD46, a primate-specific receptor for measles virus". Trends Microbiol. 2 (9): 312–8. doi:10.1016/0966-842X(94)90447-2. PMID 7529121.
  11. Gaggar A, Shayakhmetov, DM, Lieber A (2003). "CD46 is a cellular receptor for group B adenoviruses". Nat. Med. 9 (11): 1408–1412. doi:10.1038/nm952. PMID 14566335. S2CID 25265753.
  12. Cattaneo R (May 2004). "Four viruses, two bacteria, and one receptor: membrane cofactor protein (CD46) as pathogens' magnet". J. Virol. 78 (9): 4385–8. doi:10.1128/JVI.78.9.4385-4388.2004. PMC 387720. PMID 15078919.
  13. Arbuckle, Jesse (2011). "The molecular biology of human herpesvirus-6 latency and telomere integration". Microbes and Infection. 13 (8–9): 731–741. doi:10.1016/j.micinf.2011.03.006. PMC 3130849. PMID 21458587.
  14. Mori (2009). "Recent topics related to human herpesvirus 6 cell tropism". Cellular Microbiology. 11 (7): 1001–6. doi:10.1111/j.1462-5822.2009.01312.x. PMID 19290911. S2CID 20827342.
  15. Studebaker AW, Kreofsky CR, Pierson CR, Russell SJ, Galanis E, Raffel C (May 2010). "Treatment of medulloblastoma with a modified measles virus". Neuro Oncol. 12 (10): 1034–1042. doi:10.1093/neuonc/noq057. PMC 3018921. PMID 20494960.
  16. Su, Yang; Liu, Yue; Behrens, Christopher R.; Bidlingmaier, Scott; Lee, Nam-Kyung; Aggarwal, Rahul; Sherbenou, Daniel W.; Burlingame, Alma L.; Hann, Byron C.; Simko, Jeffry P.; Premasekharan, Gayatri (2018-09-06). "Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer". JCI Insight. 3 (17). doi:10.1172/jci.insight.121497. ISSN 0021-9738. PMC 6171802. PMID 30185663.
  17. Ruan, Weiming; Sassoon, Adam; An, Feng; Simko, Jeff P.; Liu, Bin (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. 5 (12): 2364–2373. doi:10.1074/mcp.m600246-mcp200. ISSN 1535-9476. PMID 16982673.
  18. Wang, Sinan; Li, Jun; Hua, Jun; Su, Yang; Beckford-Vera, Denis R.; Zhao, Walter; Jayaraman, Mayuri; Huynh, Tony L.; Zhao, Ning; Wang, Yung-hua; Huang, Yangjie (2021-03-01). "Molecular Imaging of Prostate Cancer Targeting CD46 Using ImmunoPET". Clinical Cancer Research. 27 (5): 1305–1315. doi:10.1158/1078-0432.CCR-20-3310. ISSN 1078-0432. PMC 7925362. PMID 33293372.
  19. Liszewski MK, Atkinson JP (2021). "Membrane cofactor protein (MCP; CD46): deficiency states and pathogen connections". Curr Opin Immunol. 72: 126–134. doi:10.1016/j.coi.2021.04.005. PMC 8123722. PMID 34004375.
  20. Lozahic S, Christiansen D, Manié S, Gerlier D, Billard M, Boucheix C, Rubinstein E (March 2000). "CD46 (membrane cofactor protein) associates with multiple beta1 integrins and tetraspans". Eur. J. Immunol. 30 (3): 900–7. doi:10.1002/1521-4141(200003)30:3<900::AID-IMMU900>3.0.CO;2-X. PMID 10741407.
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