Ternary model structural complex of C5a, C5aR2, and β-arrestin1

Complement component fragment 5a (C5a) is one of the potent proinflammatory modulators of the complement system. C5a recruits two genomically related G protein-coupled receptors (GPCRs), like C5aR1 and C5aR2, constituting a binary complex. The C5a-C5aR1/C5aR2 binary complexes involve other transducer proteins like heterotrimeric G-proteins and β-arrestins to generate the fully active ternary complexes that trigger intracellular signaling through downstream effector molecules in tissues. In the absence of structural data, we had recently developed highly refined model structures of C5aR2 in its inactive (free), meta-active (complexed to the CT-peptide of C5a), and active (complexed to C5a) state embedded to a model palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer. Compared to C5aR1, C5aR2 is established as a noncanonical GPCR, as it recruits and signals through β-arrestins rather than G-proteins. Notably, structural understanding of the ternary complex involving C5a-C5aR2-β-arrestin is currently unknown. The current study has attempted to fill the gap by generating a highly refined, fully active ternary model structural complex of the C5a-C5aR2-β-arrestin1 embedded in a model POPC bilayer. The computational modeling, 500 ns molecular dynamics (MD) studies, and the principal component analysis (PCA), including the molecular mechanics Poisson-Boltzmann surface area (MM PBSA) based data presented in this study, provide an experimentally testable hypothesis about C5a-C5aR2-β-arrestin1 extendable to other such ternary systems. The model ternary complex of C5a-C5aR2-β-arrestin1 will further enrich the current structural understanding related to the interaction of β-arrestins with the C5a-C5aR2 system.Communicated by Ramaswamy H. Sarma.