Structural biology of complement receptors

Abstract

The complement system plays crucial roles in a wide breadth of immune and inflammatory processes and is frequently cited as an etiological or aggravating factor in many human diseases, from asthma to cancer. Complement receptors encompass at least eight proteins from four structural classes, orchestrating complement-mediated humoral and cellular effector responses and coordinating the complex cross-talk between innate and adaptive immunity. The progressive increase in understanding of the structural features of the main complement factors, activated proteolytic fragments, and their assemblies have spurred a renewed interest in deciphering their receptor complexes. In this review, we describe what is currently known about the structural biology of the complement receptors and their complexes with natural agonists and pharmacological antagonists. We highlight the fundamental concepts and the gray areas where issues and problems have been identified, including current research gaps. We seek to offer guidance into the structural biology of the complement system as structural information underlies fundamental and therapeutic research endeavors. Finally, we also indicate what we believe are potential developments in the field.

Keywords: C5aR1/C5L2/C3aR; CR1/CR2; CR3/CR4; CRIg; complement; complement receptors; host-pathogen interactions; structural biology.

Figure 1

Complement receptors CR1 and CR2 are mosaic proteins built from CCP/SCR modules. (A) Structure of a prototypical CCP/SCR domain, the CR1 CCP16, taken from the structure of CR1 CCPs 15-17:C3b (PDB ID 5FO9). The domain is shown in cartoons in two orientations. The two most conserved features of CCP domains, the disulfide bonds between four conserved cysteine residues (C1-C3 and C2-C4) and a conserved tryptophan (W) residue, are shown in sticks and CPK atom colors. (B) Structure of the CR1 ectodomain (left) comprising CCPs 1-30 modeled from SAXS data (PDB ID 2Q7Z), with C3b/C4b interacting CCP domains colored in lime (C4b) and dark green (C3b/C4b). Structure of the CR1 CCPs 15-17:C3b (right) (PDB ID 5FOB) in molecular surface representation. C3b is colored according to chain (the α’ chain in red, the β chain in blue), and CR1 CCPs 15-17 is colored in dark green. (C) Structure of the CR2 ectodomain (left) comprising CCPs 1-15 modeled from SAXS data (PDB ID 2GSX), with C3b interacting CCP domains colored in cyan. Structure of the CR2 CCPs 1-2:C3d (right) (PDB ID 3OED) in molecular surface representation. C3d is colored in red, and CR2 CCPs 1-2 is colored in cyan.

Figure 2

Complement receptor CR3. (A) Cartoon and molecular surface representations of the X-ray crystallographic structure of the CR3 headpiece in complex with a nanoantibody (Nb) (PDB ID 7P2D). The α_MI domain is in the inactive, closed conformation. (B) Cartoon representation of the cryoelectron microscopy structure of the CR3 ectodomain (except for the α_MI domain) in an inactive, closed conformation (PDB ID 7USM). (C) X-ray crystallographic structure of a complex between iC3b and CR3 α_MI domain (PDB ID 7AKK) where iC3b adopts an extended conformation. The interaction between the TED/C3d domain of iC3b and CR3 α_MI is shown in two orientations related by a 90° rotation. (D) Molecular surface representation of the cryoelectron microscopy structure of the CR3 ectodomain (except for the α_MI domain) in complex with B. pertussis RTX751 toxin (PDB ID 7USL). In this structure, the CR3 ectodomain adopts a more extended conformation than in (B) through interactions with the toxin.

Figure 3

Complement receptor CR4. (A) Cartoon representation of an X-ray crystallographic structure of the CR4 ectodomain in an inactive but metastable structure that anticipates activation (PDB ID 4NEH). Two orientations related by a 90° rotation are shown. (B) As in (A) but as a molecular surface representation. Native glycan moieties are shown as white spheres.

Figure 4

Complement receptor CRIg consists of two Ig-like domains and binds the β-chain of C3b. (A) Crystallographic structure of the V-set Ig-like 1 domain of CRIg, in cartoon representation and two orientations (PDB ID 2ICC). (B) AlphaFold predicts with high confidence the structural model of the C2-type Ig-like 2 domain of CRIg (AlphaFold AF-Q9Y279-F1). The consecutive Ig-like 1 and 2 domains are shown in cartoon representation and two orientations; the orientation of the V-set Ig-like 1 matches panel A for comparison. (C) Structure of CRIg V-set Ig-like 1:C3b (PDB ID 2ICF) in molecular surface representation. C3b is colored according to chain (the α chain in red, the β chain in blue), and CRIg V-set Ig-like 1 domain is in cyan. Native glycan chains in C3b are shown in white spheres.).

Figure 5

Anaphylatoxin receptor C5aR1 in complex with C5a and conformational changes underlying activation. (A) Cryoelectron microscopy structure of C5aR1:C5a bound to heterotrimeric G protein comprising the Gα, Gβ, and Gγ subunits (shown in orange, yellow, and gold), and a stabilizing antibody (shown in gray) (PDB ID 7I65). C5aR1 is shown in green, and C5a in red. The same view is shown of the cartoon and molecular surface representations of the complex. We show a 90° rotated view of the complex on the right in molecular surface representation. (B) Superposition of the active conformation of the C5aR1:C5a complex (PDB ID 7I65) (C5aR1 in green, C5a in red) and an inactive reference structure (PDB ID 6C1Q) (C5aR1 in grey; the antagonist PMX53 is not shown for clarity). Side (left) and bottom (right) views are shown. Conformational changes are indicated by dashed lines between and labeling of structural elements that occupy distinct positions in the active versus inactive conformations.

Figure 6

Anaphylatoxin receptor C3aR in complex with C3a and conformational changes underlying activation. (A) Cryoelectron microscopy structure of C3aR:C3a bound to heterotrimeric G protein comprising the Gα, Gβ, and Gγ subunits (shown in orange, yellow, and gold), and a stabilizing antibody (shown in gray) (PDB ID 8HZ2). C3aR is shown in green, and C3a in red. The same view is shown of the cartoon and molecular surface representations of the complex. We show a 90° rotated view of the complex on the right in molecular surface representation. (B) Superposition of the active conformation of the C3aR:C3a complex (PDB ID 8HZ2) (C3aR in green, C3a in red) and an inactive reference structure (PDB ID 6C1Q) (C5aR1 in grey; the antagonist PMX53 is not shown for clarity). Side (left) and bottom (right) views are shown. Conformational changes are indicated by dashed lines between and labeling of structural elements that occupy distinct positions in the active versus inactive conformations.