Emerging Insights into the Structure and Function of Complement C5a Receptors

The complement cascade is a critical part of our innate immune system that plays a crucial role in combating pathogenic infections. Complement C5a, a potent anaphylatoxin in the complement cascade, activates two different seven transmembrane receptors, namely C5aR1 and C5aR2. C5aR1 is a prototypical GPCR, while C5aR2, which exhibits functional analogy to ACKRs, does not exhibit any functional coupling to G proteins but engages βarrs upon activation. Crystal structures of C5aR1 in complex with antagonists have provided important insights into ligand–receptor interaction and a potential template for novel ligand discovery. Ligand-specific functional bias at C5aR1 has been discovered recently that offers a potential framework for better therapeutic intervention. 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. 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. ligands that activate the receptors and promote their coupling to downstream signal transducers and effectors resulting in signaling responses. ligands that bind to the receptor but stabilize an inactive conformation, thereby not allowing downstream signaling. multifunctional adaptor proteins that are recruited to agonist-activated and phosphorylated GPCRs, and play important roles in their desensitization, endocytosis, and signaling. an integral part of the innate immune response involved in the process of homeostasis, inflammation, and defense against pathogens, also known as the complement cascade. seven transmembrane receptors ubiquitously expressed in the plasma membrane of cells, and they recognize a broad spectrum of signals. heterotrimeric guanine nucleotide binding proteins consisting of the α, β, and γ subunits, and are the primary signal transducers downstream of GPCRs. ligands that reduce the basal activity of the receptors by stabilizing an inactive conformation of the receptor. an assembly of several complement proteins formed on the membrane of the pathogen upon the activation of host complement system, also referred to as the terminal complement complex. binding pocket on the receptor that accommodates the natural agonist is referred to as orthosteric binding pocket while any other ligand binding interface is typically referred to as allosteric binding pocket.