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

• Published in: Cell reports (Cambridge) Vol. 28; no. 10; pp. 2567 - 2580.e6
• Main Authors: 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, McCorvy, John D., Baier, Leslie J., Sham, Yuk Y., Bartolomucci, Alessandro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.09.2019; Elsevier
• Subjects: 3T3-L1 Cells; Adipocytes - metabolism; Adipose Tissue, White - metabolism; Adrenergic Agents - pharmacology; Adult; Amino Acid Motifs; Animals; Calcium - metabolism; Computer Simulation; drug discovery; Evolution, Molecular; Extracellular Space - chemistry; granin peptides; Humans; innate immunity; Lipolysis; lipolytic catecholamine resistance; Male; Mice; Mice, Inbred C57BL; Models, Biological; Neuropeptides - metabolism; obesity; Obesity - metabolism; Peptide Fragments - metabolism; Protein Binding - drug effects; Receptors, Complement - metabolism; Structural Homology, Protein; transient receptor potential channel; VGF; VGF; drug discovery; innate immunity; lipolytic catecholamine resistance; transient receptor potential channel; granin peptides; obesity
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.07.101

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. [Display omitted] •TLQP-21 binds to C3aR1 and potentiates lipolysis via intracellular calcium•A cluster of mutations was identified in C3aR1 and TLQP-21 in Murinae•These mutations result in enhanced binding affinity and pharmacological potency•Mouse TLQP-21 enhances adrenergic-receptor-induced lipolysis in human adipocytes GPCRs and neuropeptide ligands are under intense evolutionary pressure and are major pharmacological targets. Sahu et al. identify a cluster of mutations within the C3aR1 receptor and the TLQP-21 peptide in the Murinae subfamily of rodents, resulting in enhanced binding affinity and potency, leading to potentiation of adrenergic-receptor-induced lipolysis.