Peptide/Receptor Co-evolution Explains the Lipolytic Function of the Neuropeptide TLQP-21

Bhavani S. Sahu, Pedro Rodriguez, Megin E. Nguyen, Ruijun Han, Cheryl Cero, Maria Razzoli, Paolo Piaggi, Lauren J. Laskowski, Mihaela Pavlicev, Louis Muglia, Sushil K. Mahata, Scott O'Grady, John D. McCorvy, Leslie J. Baier, Yuk Y. Sham, Alessandro Bartolomucci

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Structural and functional diversity of peptides and GPCR result from long evolutionary processes. Even small changes in sequence can alter receptor activation, affecting therapeutic efficacy. We conducted a structure-function relationship study on the neuropeptide TLQP-21, a promising target for obesity, and its complement 3a receptor (C3aR1). After having characterized the TLQP-21/C3aR1 lipolytic mechanism, a homology modeling and molecular dynamics simulation identified the TLQP-21 binding motif and C3aR1 binding site for the human (h) and mouse (m) molecules. mTLQP-21 showed enhanced binding affinity and potency for hC3aR1 compared with hTLQP-21. Consistently, mTLQP-21, but not hTLQP-21, potentiates lipolysis in human adipocytes. These findings led us to uncover five mutations in the C3aR1 binding pocket of the rodent Murinae subfamily that are causal for enhanced calculated affinity and measured potency of TLQP-21. Identifying functionally relevant peptide/receptor co-evolution mechanisms can facilitate the development of innovative pharmacotherapies for obesity and other diseases implicating GPCRs.

Original languageEnglish (US)
Pages (from-to)2567-2580.e6
JournalCell reports
Volume28
Issue number10
DOIs
StatePublished - Sep 3 2019

Bibliographical note

Funding Information:
This study was supported by NIH / NIDDK DK102496 and DK117504 (to A.B.), a JCSTF-180217 travelling research fellowship from the Company of Biologists (to B.S.S.), AI128729 and AES0016096 (to S.O.), and Department of Veterans Affairs I01BX000323 (to S.K.M.). This study was also supported by the Intramural Program of the NIDDK , NIH (to L.B.), and BT-/RLF/Re-entry/38/2016 , Department of Biotechnology , Government of India (to B.S.S.). The mouse study was conducted at the IBP Phenotyping Core (University of Minnesota).

Funding Information:
This study was supported by NIH/NIDDK DK102496 and DK117504 (to A.B.), a JCSTF-180217 travelling research fellowship from the Company of Biologists (to B.S.S.), AI128729 and AES0016096 (to S.O.), and Department of Veterans Affairs I01BX000323 (to S.K.M.). This study was also supported by the Intramural Program of the NIDDK, NIH (to L.B.), and BT-/RLF/Re-entry/38/2016, Department of Biotechnology, Government of India (to B.S.S.). The mouse study was conducted at the IBP Phenotyping Core (University of Minnesota). B.S.S. R.H. C.C. M.R. and P.R. performed the in vitro and in vivo experiments. M.E.N. and Y.Y.S. performed computational modeling and evolutionary analysis. M.P. and L.M. performed the Bayesian analysis. S.K.M. provided reagents and support for the Calcium45 experiments. S.O. provided reagents and support for the Calcium influx experiments. P.P. and L.J.B. collected and analyzed the human data. L.J.L. and J.D.M. performed site-directed mutagenesis and the ?-arrestin assay. B.S.S. R.H. P.R. M.E.N. J.D.M. Y.Y.S. and A.B. analyzed the data. B.S.S. Y.Y.S. and A.B. wrote the manuscript with input from all other coauthors. A.B. conceptualized the study. The authors declare no competing interests.

Publisher Copyright:
© 2019 The Author(s)

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

  • VGF
  • drug discovery
  • granin peptides
  • innate immunity
  • lipolytic catecholamine resistance
  • obesity
  • transient receptor potential channel

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