| Structural highlights
3inb is a 4 chain structure with sequence from Human and Mease. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Related: | 2rkc, 2zb5, 2zb6, 1ckl, 2o39 |
| Gene: | H (MEASE), CD46, MCP, MIC10 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[MCP_HUMAN] Defects in CD46 are a cause of susceptibility to hemolytic uremic syndrome atypical type 2 (AHUS2) [MIM:612922]. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype. Patients with CD46 mutations seem to have an overall better prognosis compared to patients carrying CFH mutations.[1] [2] [3] [4] [5]
Function
[HEMA_MEASE] Attaches the virus to cell receptors and thereby initiating infection. Binding of H protein to the receptor induces a conformational change that allows the F protein to trigger virion/cell membranes fusion. May use human CD46 and/or SLAMF1 as receptors for viral entry into the cell. The high degree of interaction between H and MCP/CD46 results in down-regulation of the latter from the surface of infected cells, rendering them more sensitive to c3b-mediated complement lysis.[6] [MCP_HUMAN] Acts as a cofactor for complement factor I, a serine protease which protects autologous cells against complement-mediated injury by cleaving C3b and C4b deposited on host tissue. May be involved in the fusion of the spermatozoa with the oocyte during fertilization. Also acts as a costimulatory factor for T-cells which induces the differentiation of CD4+ into T-regulatory 1 cells. T-regulatory 1 cells suppress immune responses by secreting interleukin-10, and therefore are thought to prevent autoimmunity. A number of viral and bacterial pathogens seem to exploit this property and directly induce an immunosuppressive phenotype in T-cells by binding to CD46.[7] [8]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The highly contagious measles virus infects millions of individuals worldwide, causing serious disease in children of developing countries. Infection is initiated by attachment of the measles virus hemagglutinin (MV-H), a glycoprotein anchored to the virus envelope, to the host cell receptors CD46 or signaling lymphocyte activation molecule (SLAM). Here we report the crystal structure of MV-H in complex with a CD46 protein spanning the two N-terminal domains. A unique groove at the side of the MV-H beta-propeller domain, which is absent in homologous paramyxovirus attachment proteins, engages residues in both CD46 domains. Key contacts involve a protruding loop in the N-terminal CD46 domain that carries two sequential proline residues (PP motif) and penetrates deeply into a hydrophobic socket in MV-H. We identify a similar PP motif in SLAM, defining a common measles virus recognition epitope in the CD46 and SLAM receptor proteins.
Structure of the measles virus hemagglutinin bound to the CD46 receptor.,Santiago C, Celma ML, Stehle T, Casasnovas JM Nat Struct Mol Biol. 2010 Jan;17(1):124-9. Epub 2009 Dec 13. PMID:20010840[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Noris M, Brioschi S, Caprioli J, Todeschini M, Bresin E, Porrati F, Gamba S, Remuzzi G. Familial haemolytic uraemic syndrome and an MCP mutation. Lancet. 2003 Nov 8;362(9395):1542-7. PMID:14615110 doi:10.1016/S0140-6736(03)14742-3
- ↑ Richards A, Kemp EJ, Liszewski MK, Goodship JA, Lampe AK, Decorte R, Muslumanoglu MH, Kavukcu S, Filler G, Pirson Y, Wen LS, Atkinson JP, Goodship TH. Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12966-71. Epub 2003 Oct 17. PMID:14566051 doi:10.1073/pnas.2135497100
- ↑ Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F, Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006 Aug 15;108(4):1267-79. Epub 2006 Apr 18. PMID:16621965 doi:10.1182/blood-2005-10-007252
- ↑ Esparza-Gordillo J, Jorge EG, Garrido CA, Carreras L, Lopez-Trascasa M, Sanchez-Corral P, de Cordoba SR. Insights into hemolytic uremic syndrome: segregation of three independent predisposition factors in a large, multiple affected pedigree. Mol Immunol. 2006 Apr;43(11):1769-75. Epub 2006 Jan 18. PMID:16386793 doi:10.1016/j.molimm.2005.11.008
- ↑ Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat. 2010 Jun;31(6):E1445-60. doi: 10.1002/humu.21256. PMID:20513133 doi:10.1002/humu.21256
- ↑ Galbraith SE, Tiwari A, Baron MD, Lund BT, Barrett T, Cosby SL. Morbillivirus downregulation of CD46. J Virol. 1998 Dec;72(12):10292-7. PMID:9811778
- ↑ Astier A, Trescol-Biemont MC, Azocar O, Lamouille B, Rabourdin-Combe C. Cutting edge: CD46, a new costimulatory molecule for T cells, that induces p120CBL and LAT phosphorylation. J Immunol. 2000 Jun 15;164(12):6091-5. PMID:10843656
- ↑ Kemper C, Chan AC, Green JM, Brett KA, Murphy KM, Atkinson JP. Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature. 2003 Jan 23;421(6921):388-92. PMID:12540904 doi:10.1038/nature01315
- ↑ Santiago C, Celma ML, Stehle T, Casasnovas JM. Structure of the measles virus hemagglutinin bound to the CD46 receptor. Nat Struct Mol Biol. 2010 Jan;17(1):124-9. Epub 2009 Dec 13. PMID:20010840 doi:10.1038/nsmb.1726
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