Structure of the Extracellular Portion of CD46 Provides Insights into Its Interactions with Complement Proteins and Pathogens

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Abstract
The 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. The human membrane cofactor protein (MCP, CD46) is expressed on all nucleated cells and serves as a marker that prevents host cells from destruction by the immune system. It functions as a cofactor that helps to inactivate the C3b and C4b molecules, which are central components of the complement system. In addition to its role in regulation complement activation, CD46 is also used by a large number of pathogens, including measles virus and adenovirus, as a receptor to allow these pathogens to attach to the cell surface and initiate an infection. We have determined the three-dimensional structure of the bulk of the extracellular region of CD46 using X-ray crystallography. This structure provides detailed information about the location of previously identified residues that play a role in the interactions with C3b, C4b, and several pathogens, advancing an understanding of the function of the CD46 protein as a host and pathogen receptor. Moreover, the structure also reveals an unexpected, bent conformation of the protein that has implications for how the binding sites are presented at the cell surface.