3o8e
From Proteopedia
Structure of extracelllar portion of CD46 in complex with Adenovirus type 11 knob
Structural highlights
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[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.[6] [7] Publication Abstract from PubMedThe human membrane cofactor protein (MCP, CD46) is a central component of the innate immune system. CD46 protects autologous cells from complement attack by binding to complement proteins C3b and C4b and serving as a cofactor for their cleavage. Recent data show that CD46 also plays a role in mediating acquired immune responses, and in triggering autophagy. In addition to these physiologic functions, a significant number of pathogens, including select adenoviruses, measles virus, human herpes virus 6 (HHV-6), Streptococci, and Neisseria, use CD46 as a cell attachment receptor. We have determined the crystal structure of the extracellular region of CD46 in complex with the human adenovirus type 11 fiber knob. Extracellular CD46 comprises four short consensus repeats (SCR1-SCR4) that form an elongated structure resembling a hockey stick, with a long shaft and a short blade. Domains SCR1, SCR2 and SCR3 are arranged in a nearly linear fashion. Unexpectedly, however, the structure reveals a profound bend between domains SCR3 and SCR4, which has implications for the interactions with ligands as well as the orientation of the protein at the cell surface. This bend can be attributed to an insertion of five hydrophobic residues in a SCR3 surface loop. Residues in this loop have been implicated in interactions with complement, indicating that the bend participates in binding to C3b and C4b. The structure provides an accurate framework for mapping all known ligand binding sites onto the surface of CD46, thereby advancing an understanding of how CD46 acts as a receptor for pathogens and physiologic ligands of the immune system. Structure of the extracellular portion of CD46 provides insights into its interactions with complement proteins and pathogens.,Persson BD, Schmitz NB, Santiago C, Zocher G, Larvie M, Scheu U, Casasnovas JM, Stehle T PLoS Pathog. 2010 Sep 30;6(9). pii: e1001122. PMID:20941397[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
Categories: Homo sapiens | Human adenovirus 11 | Casasnovas, J M | Persson, B D | Schmitz, N B | Stehle, T | Adenovirus | Cd46 | Cell adhesion - immune system complex | Cell adhesion-immune system complex | Cell adhesion-immunity complex | Complement control protein | Fiber knob | Short consensus repeat | Virus-receptor interaction
