TY - JOUR
T1 - Regulators of complement activity mediate inhibitory mechanisms through a common C3b-binding mode
AU - Forneris, Federico
AU - Wu, Jin
AU - Xue, Xiaoguang
AU - Ricklin, Daniel
AU - Lin, Zhuoer
AU - Sfyroera, Georgia
AU - Tzekou, Apostolia
AU - Volokhina, Elena
AU - Granneman, Joke C.M.
AU - Hauhart, Richard
AU - Bertram, Paula
AU - Liszewski, M. Kathryn
AU - Atkinson, John P.
AU - Lambris, John D.
AU - Gros, Piet
N1 - Publisher Copyright:
© 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
PY - 2016/5/17
Y1 - 2016/5/17
N2 - 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. Synopsis Complement activity is controlled by regulators binding to C3b or C4b. Analysis of five C3b regulator structures reveals that both decay-acceleration and cofactor activity depend on a common C3b-regulator binding mode. Crystal structures reveal C3b binding of four human and viral complement regulators Common mode of C3b binding underlies decay-acceleration and cofactor activity Extensive variations in interaction details explain diverse characteristics of regulators C3b-regulator structures provide basis for understanding disease-related mutations Structural insights into how complement factor C3b binds to human and viral regulators of complement activation aid our understanding of disease-related mutations and SNPs affecting complement control.
AB - 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. Synopsis Complement activity is controlled by regulators binding to C3b or C4b. Analysis of five C3b regulator structures reveals that both decay-acceleration and cofactor activity depend on a common C3b-regulator binding mode. Crystal structures reveal C3b binding of four human and viral complement regulators Common mode of C3b binding underlies decay-acceleration and cofactor activity Extensive variations in interaction details explain diverse characteristics of regulators C3b-regulator structures provide basis for understanding disease-related mutations Structural insights into how complement factor C3b binds to human and viral regulators of complement activation aid our understanding of disease-related mutations and SNPs affecting complement control.
KW - cofactor activity
KW - complement
KW - decay-accelerating activity
KW - immune evasion
KW - regulators of complement activity
UR - http://www.scopus.com/inward/record.url?scp=84961792791&partnerID=8YFLogxK
U2 - 10.15252/embj.201593673
DO - 10.15252/embj.201593673
M3 - Article
C2 - 27013439
AN - SCOPUS:84961792791
SN - 0261-4189
VL - 35
SP - 1133
EP - 1149
JO - EMBO Journal
JF - EMBO Journal
IS - 10
ER -