Structural insights on complement activation

Abstract

21 p.-6 fig. ; The proteolytic cleavage of C3 to generate C3b is the central and most important step in the activation of Complement, a major component of innate immunity. The comparison of the crystal structures of C3 and C3b illustrates large conformational changes during the transition from C3 to C3b. Exposure of a reactive thio-ester group allows C3b to bind covalently to surfaces such as pathogens or apoptotic cellular debris. The displacement of the thio-ester containing domain (TED) exposes hidden surfaces that mediate the interaction with complement factor B to assemble the C3- convertase of the alternative pathway (AP). In addition, the displacement of the TED domain and its interaction with the macroglobulin 1 (MG1) domain generates a extended surface in C3b where the complement regulators factor H (FH), decay accelerating factor (DAF), membrane cofactor protein (MCP) and complement receptor 1 (CR1) can bind, mediating accelerated decay of the AP C3-convertase and proteolytic inactivation of C3b. In the last few years, evidence has accumulated revealing that the structure of C3b in solution is significantly more flexible than anticipated. We review our current knowledge on C3b structural flexibility to propose a general model where the TED domain can display a collection of conformations around the MG ring, as well as a few specialised positions where the TED is held in one of several fixed locations. Importantly, this conformational heterogeneity in C3b impacts complement regulation, by affecting the interaction with regulators. ; This work was funded by the Spanish Government (SAF2011- 22988 and SAF2014-52301-R to OL;SAF2011-26583 to SRdeC), the EU (Eurenomics to SRdC) and by the Government of the Autonomous Region of Madrid (S2010/BMD-2316 to OL and SRdC). ; Peer reviewed