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
Affiliations
Bhavani S. Sahu
Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th St. SE, Minneapolis, MN, USA
Pedro Rodriguez
Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th St. SE, Minneapolis, MN, USA
Megin E. Nguyen
Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th St. SE, Minneapolis, MN, USA
Ruijun Han
Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th St. SE, Minneapolis, MN, USA
Cheryl Cero
Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th St. SE, Minneapolis, MN, USA
Maria Razzoli
Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th St. SE, Minneapolis, MN, USA
Paolo Piaggi
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Phoenix, AZ, USA
Lauren J. Laskowski
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Mihaela Pavlicev
Division of Human Genetics, Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
Louis Muglia
Division of Human Genetics, Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
Sushil K. Mahata
VA San Diego Healthcare System, San Diego, CA, USA; Department of Medicine, University of California at San Diego, La Jolla, CA, USA
Scott O’Grady
Department of Animal Science, University of Minnesota, 480 Haecker Hall, 1364 Eckles Avenue, St. Paul, MN, USA
John D. McCorvy
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Leslie J. Baier
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Phoenix, AZ, USA
Yuk Y. Sham
Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th St. SE, Minneapolis, MN, USA; Bioinformatics and Computational Biology Program, University of Minnesota, Minneapolis, MN, USA
Alessandro Bartolomucci
Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th St. SE, Minneapolis, MN, USA; Corresponding author
Summary: 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. : 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. Keywords: VGF, lipolytic catecholamine resistance, granin peptides, drug discovery, obesity, innate immunity, transient receptor potential channel
