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 M O'Grady, John D. McCorvy, Leslie J. Baier, Yuk Y Sham, Alessandro Bartolomucci

Research output: Contribution to journalArticle

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

Fingerprint

Complement C3a
Drug therapy
Peptide Receptors
Neuropeptides
Molecular dynamics
Obesity
Chemical activation
Binding Sites
Murinae
Complement Receptors
Peptides
Molecules
Lipolysis
Computer simulation
Molecular Dynamics Simulation
Adipocytes
Rodentia
Drug Therapy
Mutation
Therapeutics

Keywords

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

PubMed: MeSH publication types

  • Journal Article

Cite this

Peptide/Receptor Co-evolution Explains the Lipolytic Function of the Neuropeptide TLQP-21. / Sahu, Bhavani S.; Rodriguez, Pedro; Nguyen, Megin E.; Han, Ruijun; Cero, Cheryl; Razzoli, Maria; Piaggi, Paolo; Laskowski, Lauren J.; Pavlicev, Mihaela; Muglia, Louis; Mahata, Sushil K.; O'Grady, Scott M; McCorvy, John D.; Baier, Leslie J.; Sham, Yuk Y; Bartolomucci, Alessandro.

In: Cell reports, Vol. 28, No. 10, 03.09.2019, p. 2567-2580.e6.

Research output: Contribution to journalArticle

Sahu, BS, Rodriguez, P, Nguyen, ME, Han, R, Cero, C, Razzoli, M, Piaggi, P, Laskowski, LJ, Pavlicev, M, Muglia, L, Mahata, SK, O'Grady, SM, McCorvy, JD, Baier, LJ, Sham, YY & Bartolomucci, A 2019, 'Peptide/Receptor Co-evolution Explains the Lipolytic Function of the Neuropeptide TLQP-21', Cell reports, vol. 28, no. 10, pp. 2567-2580.e6. https://doi.org/10.1016/j.celrep.2019.07.101
Sahu, Bhavani S. ; Rodriguez, Pedro ; Nguyen, Megin E. ; Han, Ruijun ; Cero, Cheryl ; Razzoli, Maria ; Piaggi, Paolo ; Laskowski, Lauren J. ; Pavlicev, Mihaela ; Muglia, Louis ; Mahata, Sushil K. ; O'Grady, Scott M ; McCorvy, John D. ; Baier, Leslie J. ; Sham, Yuk Y ; Bartolomucci, Alessandro. / Peptide/Receptor Co-evolution Explains the Lipolytic Function of the Neuropeptide TLQP-21. In: Cell reports. 2019 ; Vol. 28, No. 10. pp. 2567-2580.e6.
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