Putting the structure into complement

Abstract

In a field where structure has finally begun to have a real impact, a series of new structures over the last two years have further extended our understanding of some of the critical regulatory events of the complement system. Notably, information has begun to flow from larger assemblies of components which allow insight into the often transient assemblies critical to complement regulation at the cell surface. This review will summarise the key structures determined since the last International Complement Workshop and the insights these have given us, before highlighting some questions that still require molecular frameworks to drive understanding.

Figure 1

(a) The mechanism for decay acceleration of the C3bBb remains unclear despite the large structural advances since simple overlay of structures for C3bBb (Rooijakkers et al., 2009) and C3bFH_1-4 (Wu et al., 2009) reveals the two structures are incompatible (due to clashes between FH_1-4 and Bb) without revealing what conformational changes are required to promote dissociation of Bb from the C3bBb complex. (b) Recent structures allow construction of pseudo-atomic models for the complex of C3b/FH_1-4/FH_18-20/FI (Kajander et al., 2011; Morgan et al., 2012; Morgan et al., 2011; Roversi et al., 2011; Wu et al., 2009) showing the context in which the first cleavage event of co-factor regulation occurs. (c) Electron microscopy volumes for sC5b9 and atomic structures for C5b6 (Hadders et al., 2012), and C8 (Lovelace et al., 2011) suggest that the membrane attack complex pore assembles MACPF domains in an analogous fashion to bacterial CDC pores (e.g. perfringolysin O (Gilbert et al., 1998; Rossjohn et al., 1997)) rather than as proposed for perforin pores (Law et al., 2010). All pictures drawn using PyMol (www.pymol.org).