C5aR2 receptor: The genomic twin of the flamboyant C5aR1

Abstract

The complement fragment C5a is one of the most potent proinflammatory glycoproteins liberated by the activation of the biochemical cascade of the complement system. C5a is established to interact with a set of genomically related transmembrane receptors, like C5aR1 (CD88, C5aR) and C5aR2 (GPR77, C5L2) with comparable affinity. The C5aR1 is a classical G‐protein‐coupled receptor (GPCR), whereas C5aR2 is a nonclassical GPCR that tailors immune cell activity potentially through β‐arrestins rather than G‐proteins. Currently, the exact function of the C5aR2 is actively debated in the context of C5aR1, even though both C5aR1 and C5aR2 are coexpressed on myriads of tissues. The functional relevance of C5aR2 appears to be context‐dependent compared to the C5aR1, which has received enormous attention for its role in both acute and chronic inflammatory diseases. In addition, the structure of C5aR2 and its interaction specificity toward C5a is not structurally elucidated in the literature so far. The current study has attempted to close the gap by generating highly refined model structures of C5aR2, respectively in free (inactive), complexed to C‐terminal peptide of C5a (meta‐active) and the C5a (active), embedded to a model palmitoyl‐2‐oleoyl‐sn‐glycero‐3‐phosphocholine bilayer. The computational modeling and the 1.5‐μs molecular dynamics data presented in the current study are expected to further enrich the understanding of C5a–C5aR2 interaction compared to C5a–C5aR1, which will surely help in elaborating the currently debated biological function of C5aR2 better in the foreseeable future.

Neutraligands of C5a can potentially occlude the interaction of C5a with the complement receptors C5aR1 and C5aR2

“…This observation is in sync with the studies made for the ECL2 peptide of C5aR1 earlier, which was later evidenced in the crystal structure of thermostabilized C5aR1 24 . Overall, the observation made for the NT‐peptides and the ECL2 peptide of C5aR2 is in agreement with the model structure of C5aR2 (Figure 2) described earlier 16 …”

“…The highly refined model structural complex of C5a‐C5aR2, illustrated in Figure 2, represents the interaction of C5a with C5aR2, which has been elaborated in detail recently 16 . The C5a‐C5aR2 model postulated that the extracellular surface involving the NT‐region (M1‐D32) and the ECL2 region (Y172‐T196) of C5aR2 make a substantial energetic contribution in the binding of C5a.…”

“…24 Overall, the observation made for the NT-peptides and the ECL2 peptide of C5aR2 is in agreement with the model structure of C5aR2 (Figure 2) described earlier. 16…”

“…15 Similarly, the two-site binding structural model complex of the C5a-C5aR2 system has been elaborated very recently. 16 In the current study, major synthetic peptide fragments of C5aR2, such as the NT-peptide and its mutants (codenamed as SR12, SR13, and SR15), including the extracellular loop 2 (ECL2) peptide (codenamed as SR2), are subjected to biophysical evaluation against the recombinant human C5a to establish the C5a-C5aR2 model complex in light of C5a-C5aR1 system. In addition, we had earlier demonstrated that selected small-molecule drugs such as raloxifene and prednisone could act as neutraligands by binding and inducing conformational changes in C5a, which can affect the interaction of C5a with its receptors.…”

“…Nevertheless, a highly refined model structural complex of the C5a‐C5aR1 system embedded in the model 1‐palmitoyl‐2‐oleoyl‐sn‐glycero‐3‐phosphocholine bilayer was generated earlier 14 and further validated by recruiting the major peptide fragments (NT‐peptide and ECL2 peptide) of C5aR1 against C5a through biophysical studies 15 . Similarly, the two‐site binding structural model complex of the C5a‐C5aR2 system has been elaborated very recently 16 . In the current study, major synthetic peptide fragments of C5aR2, such as the NT‐peptide and its mutants (codenamed as SR12, SR13, and SR15), including the extracellular loop 2 (ECL2) peptide (codenamed as SR2), are subjected to biophysical evaluation against the recombinant human C5a to establish the C5a‐C5aR2 model complex in light of C5a‐C5aR1 system.…”