Regulators of complement activity mediate inhibitory mechanisms through a common C3b-binding mode

EMBO J. 2016 May 17;35(10):1133-49. doi: 10.15252/embj.201593673. Epub 2016 Mar 24.


Regulators of complement activation (RCA) inhibit complement-induced immune responses on healthy host tissues. We present crystal structures of human RCA (MCP, DAF, and CR1) and a smallpox virus homolog (SPICE) bound to complement component C3b. Our structural data reveal that up to four consecutive homologous CCP domains (i-iv), responsible for inhibition, bind in the same orientation and extended arrangement at a shared binding platform on C3b. Large sequence variations in CCP domains explain the diverse C3b-binding patterns, with limited or no contribution of some individual domains, while all regulators show extensive contacts with C3b for the domains at the third site. A variation of ~100° rotation around the longitudinal axis is observed for domains binding at the fourth site on C3b, without affecting the overall binding mode. The data suggest a common evolutionary origin for both inhibitory mechanisms, called decay acceleration and cofactor activity, with variable C3b binding through domains at sites ii, iii, and iv, and provide a framework for understanding RCA disease-related mutations and immune evasion.

Keywords: cofactor activity; complement; decay‐accelerating activity; immune evasion; regulators of complement activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • CD55 Antigens / chemistry
  • CD55 Antigens / metabolism
  • Complement Activation
  • Complement C3b / chemistry*
  • Complement C3b / metabolism*
  • Humans
  • Membrane Cofactor Protein / chemistry
  • Membrane Cofactor Protein / metabolism
  • Protein Domains
  • Receptors, Complement 3b / chemistry
  • Receptors, Complement 3b / metabolism
  • Viral Matrix Proteins / chemistry
  • Viral Matrix Proteins / metabolism


  • CD46 protein, human
  • CD55 Antigens
  • CR1 protein, human
  • Membrane Cofactor Protein
  • Receptors, Complement 3b
  • SPICE protein, variola virus
  • Viral Matrix Proteins
  • Complement C3b