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Peptide/Receptor Co-evolution Explains the Lipolytic Function of the Neuropeptide TLQP-21. Cell Rep 2019 Sep 03;28(10):2567-2580.e6

Date

09/05/2019

Pubmed ID

31484069

Pubmed Central ID

PMC6753381

DOI

10.1016/j.celrep.2019.07.101

Scopus ID

2-s2.0-85071223181 (requires institutional sign-in at Scopus site)   20 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.

Author List

Sahu BS, Rodriguez P, Nguyen ME, Han R, Cero C, Razzoli M, Piaggi P, Laskowski LJ, Pavlicev M, Muglia L, Mahata SK, O'Grady S, McCorvy JD, Baier LJ, Sham YY, Bartolomucci A

Author

John McCorvy PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

3T3-L1 Cells
Adipocytes
Adipose Tissue, White
Adrenergic Agents
Adult
Amino Acid Motifs
Animals
Calcium
Computer Simulation
Evolution, Molecular
Extracellular Space
Humans
Lipolysis
Male
Mice
Mice, Inbred C57BL
Models, Biological
Neuropeptides
Obesity
Peptide Fragments
Protein Binding
Receptors, Complement
Structural Homology, Protein