Structural and functional anatomy of the globular domain of complement protein C1q

Abstract

C1q is the first subcomponent of the classical pathway of the complement system and a major connecting link between innate and acquired immunity. As a versatile charge pattern recognition molecule, C1q is capable of engaging a broad range of ligands via its heterotrimeric globular domain (gC1q) which is composed of the C-terminal regions of its A (ghA), B (ghB) and C (ghC) chains. Recent studies using recombinant forms of ghA, ghB and ghC have suggested that the gC1q domain has a modular organization and each chain can have differential ligand specificity. The crystal structure of the gC1q, molecular modeling and protein engineering studies have combined to illustrate how modular organization, charge distribution and the spatial orientation of the heterotrimeric assembly offer versatility of ligand recognition to C1q. Although the biochemical and structural studies have provided novel insights into the structure-function relationships within the gC1q domain, they have also raised many unexpected issues for debate.

Fig. 1

Schematic illustration of the overall fit between gC1q [4] and one pentameric molecule of CRP [31]. (a) The separation and relative orientation of the two molecules are arbitrary with no specific interactions between the two implied. Highlighted on the CRP molecule are the key residues (Asp¹¹², Lys¹¹⁴, Tyr¹⁷⁵) shown by mutagenesis to be involved in the interaction with gC1q [45]. (b) Highlighted on the gC1q molecule (ghA shown in blue, ghB in green and ghC in red) are the residues which interact with CRP following modeling procedures. The starting CRP–gC1q model was designed to facilitate exploration of the potential gC1q interaction with CRP Asp¹¹² and Tyr¹⁷⁵ [4]. The gC1q residues shown are ghB–Tyr¹⁷⁵, ghA–Lys²⁰⁰ and ghA–Trp¹⁴⁷. Figure drawn using MOLSCRIPT [137].

Fig. 2

Conserved and variable residues in the gC1q domain. The most conserved residues in the modules ghA, ghB and ghC appear to lie in the lower half of the gC1q domain and towards the subunit–subunit interface (A–C). This core region is shared by all three modules. This is consistent with the role of the lower region of the gC1q domain in being the nucleating center for heterotrimer assembly. The variable residues are markedly different in each module (D–F). Several highly variable residues are labeled. The color-coding for the residues is given below the images. Each color corresponds to a particular rank given by ConSurf. The figure also illustrates how the gC1q domain family has used a common structural core supplanted with variable loop regions to achieve functional diversity.

Fig. 3

Domain architecture of proteins containing a gC1q signature domain. The gC1q signature domains are also found in variety of collagen and non-collagen containing proteins, which constitute a novel C1q family. The gC1q are either homotrimeric (type VIII and X collagen, multimerin, ACRP30, and saccular collagen), or heterotrimeric (C1q and hibernation proteins, and probably precerebellin) structures. The crystal structure of the homotrimeric adiponectin (ACRP30/adipoQ), an adipocyte secreted adipokine which is involved in insulin resistance and fatty acid homeostasis, revealed the typical jellyroll fold which is also shared by TNF ligand superfamily members [15]. Three hibernation proteins (HP-20, -25 and -27), which disappear from serum prior to chipmunk hibernation, are also considered to regulate energy homeostasis [138]. Saccular collagen/Otolin, an inner ear structural protein in fish, may be an epicenter for otolith calcification [–141]. Precerebellin is remarkably similar to ghB module [142]. Type VIII collagen, composed of two gene products (α1 and α2), occurs as homotrimers [143]. Type X collagen is a homotrimer of three α1 (X) chains. EMILIN 1 and 2 are secretory proteins associated with elastic fibres [144]. Multimerin/EMILIN 4, found in platelets and blood vessel endothelium, can form large, variably sized homomultimers. Most members of the C1q family have a triple helical Gly–X–Y collagen repeat, except precerebellin, EMILIN 3 and 4 [145]. EMILIN 2 has a striking PspA (phage shock protein A) domain which is the major antigen of S. pneumoniae [146]. Multimerin 1/EMILIN 4 has an EGF_CA (calcium binding EGF-like domain) which are known to be involved in protein–protein interactions [147]. Two proteins of unknown function from Danio rerio having the gC1q domain also have a peroxidase/oxygenase domain. The domain architectures were obtained from the CDART database [148]. Two additional members, CORS26 and CTRP5 have been described recently. CORS26, which has been implicated in embryonic skeletal development and bore tumors, is considered a candidate susceptibility gene in the development of arthritis [149,150]. The gC1a domain of CTRP5 is considered to be involved in the formation of an extracellular hexagonal lattice between retiral pigment epithelium and Bruch's membrane [151]. A substitution mutation within the gC1q domain of CTRP5 has been linked to late-onset retinal degeneration [151].