Format

Send to

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

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

Author information

1
Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science Utrecht University, Utrecht, The Netherlands.
2
Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
3
Department of Pediatric Nephrology (830), Radboud University Medical Center, Nijmegen, The Netherlands.
4
Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.
5
Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science Utrecht University, Utrecht, The Netherlands p.gros@uu.nl.

Abstract

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

PMID:
27013439
PMCID:
PMC4868954
DOI:
10.15252/embj.201593673
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center