Conformational variants of the ternary complex of C5a, C5aR1, and G-protein

Abstract

The complement component fragment 5a (C5a) binds and activates two complement receptors like C5aR1 and C5aR2, which play a significant role in orchestrating the proinflammatory function of C5a in tissues through the recruitment of heterotrimeric G-proteins and β-arrestins. Dysregulation of the complement induces excessive production of C5a, which triggers aberrant activation of the C5a-C5aR1-G-protein and C5a-C5aR2-β-arrestin signalling axes in tissues, contributing to the pathology of numerous immune-inflammatory diseases. Thus, understanding the interaction of C5a with C5aR1 and C5aR2, as well as the interaction of G-protein and β-arrestins, respectively, with C5a-C5aR1 and C5a-C5aR2, holds tremendous therapeutic value. In the absence of structural data, we have previously elaborated the binary complexes of C5a-C5aR1 and C5a-C5aR2, as well as the ternary complex of C5a-C5aR2-β-arrestin1, in highly refined model structures. While our ternary model complex of C5a-C5aR1-G-protein was in progress, two cryo-electron microscopy-based ternary structural complexes of C5aR1 were made available by others. However, it is observed that the interaction of the crucial NT-peptide of C5aR1 with C5a, including the portion of the G⍺_i-subunit that harbors the switch-I region, is not fully resolved in both complexes. The current study addresses the issues and provides two highly refined alternative model ternary complexes of C5a-C5aR1-G-protein. The study highlights the conformational heterogeneity in C5aR1 by comparing the two conformational variants of the model ternary complex in the context of C5a-C5aR2-β-arrestin1 for further devising methods and molecules targeting both surface and intracellular C5aR1/C5aR2 for effectively mitigating the proinflammatory role of C5a in various disease settings.

Communicated by Ramaswamy H. Sarma

Keywords:

• Complement receptor
• C5aR1/C5aR2 receptor
• ternary complex
• conformational heterogeneity
• molecular dynamics

Acknowledgment

The use of the supercomputing facility at CDAC, Pune, is highly appreciated. PKG acknowledges the receipt of the fellowship from UGC, New Delhi.

Disclosure statement

The authors declare no competing interests.

Author contributions

P. K. G. and A. S. contributed to the computational modelling and MD studies. P. K. G., A. S., and S. R. analyzed the data. P. K. G. and A. S. prepared the figures. S. R. wrote the manuscript and conceived the idea for the project.

Data and software availability

Research data is being managed appropriately. All the software used in the study is duly licensed or freely available to the academic community.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.