Emerging Insights into the Structure and Function of Complement C5a Receptors

Complement factor C5a is an integral constituent of the complement cascade critically involved in the innate immune response, and it exerts its functions via two distinct receptors, C5aR1 and C5aR2. While C5aR1 is a prototypical G-protein-coupled receptor (GPCR), C5aR2 lacks functional coupling to heterotrimeric G proteins, although both receptors efficiently recruit β arrestins (βarrs). Here, we discuss the recent studies providing direct structural details of ligand-receptor interactions, and a framework of functional bias in this system, including the differences in terms of structural motifs and transducer coupling. We also discuss the functional analogy of C5aR2 with the atypical chemokine receptors (ACKRs), and highlight the future directions to elucidate the mechanistic basis of the functional divergence of these receptors activated by a common natural agonist.