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

49 Pages Posted: 26 Feb 2019 Sneak Peek Status: Review Complete

See all articles by Bhavani S. Sahu

Bhavani S. Sahu

University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology

Ruijun Han

University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology

Cheryl Cero

University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology

Maria Razzoli

University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology

Pedro Rodriguez

University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology

Megin E. Nguyen

University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology

Paolo Piaggi

National Institutes of Health - Phoenix Epidemiology and Clinical Research Branch

Mihaela Pavlicev

University of Cincinnati - Division of Human Genetics

Louis Muglia

University of Cincinnati - Division of Human Genetics

Sushil K. Mahata

Government of the United States of America - Veterans Affairs San Diego Healthcare System; University of California, San Diego (UCSD) - Department of Medicine

Scott O'Grady

University of Minnesota - St. Paul - Department of Animal Science

Leslie Baier

National Institutes of Health - Phoenix Epidemiology and Clinical Research Branch

Yuk Y. Sham

University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology

Alessandro Bartolomucci

University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology

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Abstract

Functional diversity of peptide substrates and their cognate G-Protein Coupled Receptors (GPCR) are often the result of a long evolutionary process shaped by accumulation of mutations and natural selection. Even small changes in amino acid sequence can drastically alter their binding affinity and receptor activation. Since GPCR are often investigated as molecular targets for pharmacotherapies, it is fundamentally essential to experimentally compare peptide/receptor interaction when translating promising pre-clinical therapeutic efficacy into humans. Here, we focused on the role of the Complement 3a Receptor (C3aR1) activated by the VGF-derived neuropeptide TLQP-21 in rodent and human cell system, and used molecular modelling and evolutionary analysis to infer the exact mechanism of ligand/receptor interaction. After having characterized the mechanism of TLQP-21 potentiation of beta-Adrenergic Receptor (bARs)-induced lipolysis in rodent adipocytes, we used structural data-driven homology modeling and molecular dynamics simulation to identify the TLQP-21 binding motif and its corresponding C3aR1 binding site. We found that the mouse/rat TLQP-21 had enhanced binding affinity at the human C3aR1, when compared to the human TLQP-21. Similarly, the mouse/rat TLQP-21, but not the human TLQP-21, potentiate lipolysis in human adipocytes. This surprising finding led us to reconstruct the evolution of sequence motifs within the C3aR1 binding site and the TLQP-21 pharmacophore in the Murinae sub-family of rodents, to identify changes which explain the pharmacological efficacy by virtue of enhanced hydrophobicity, and which represent stark enhancement of function for a neuropeptide that is thus rendered a potent agonist at C3aR1. Since we further demonstrated that changes in gene expression of critical nodes in TLQP-21/C3aR1-mediated lipolysis are conserved in obesity for humans and mice, and that the rodent peptide is a potent agonist at the human C3aR1, our discovery can pave the way to investigate a peptide/receptor mechanism and to develop novel pharmacotherapies for obesity and other disease conditions in which C3aR1 has been implicated.

Keywords: VGF, lipolytic catecholamine resistance, human genetic, drug discovery, obesity, innate immunity, transient receptor potential channel

Suggested Citation

Sahu, Bhavani S. and Han, Ruijun and Cero, Cheryl and Razzoli, Maria and Rodriguez, Pedro and Nguyen, Megin E. and Piaggi, Paolo and Pavlicev, Mihaela and Muglia, Louis and Mahata, Sushil K. and O'Grady, Scott and Baier, Leslie and Sham, Yuk Y. and Bartolomucci, Alessandro, Peptide/Receptor Evolution Explains the Lipolytic Function of the Neuropeptide TLQP-21 (February 26, 2019). Available at SSRN: https://ssrn.com/abstract=3341735 or http://dx.doi.org/10.2139/ssrn.3341735
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Bhavani S. Sahu

University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology

Jackson Hall 6-125
321 Church St. SE
Minneapolis, MN 55455
United States

Ruijun Han

University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology

Jackson Hall 6-125
321 Church St. SE
Minneapolis, MN 55455
United States

Cheryl Cero

University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology

Jackson Hall 6-125
321 Church St. SE
Minneapolis, MN 55455
United States

Maria Razzoli

University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology

Jackson Hall 6-125
321 Church St. SE
Minneapolis, MN 55455
United States

Pedro Rodriguez

University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology

Jackson Hall 6-125
321 Church St. SE
Minneapolis, MN 55455
United States

Megin E. Nguyen

University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology

Jackson Hall 6-125
321 Church St. SE
Minneapolis, MN 55455
United States

Paolo Piaggi

National Institutes of Health - Phoenix Epidemiology and Clinical Research Branch ( email )

4212 N 16th Street
Phoenix, AZ 85016
United States

Mihaela Pavlicev

University of Cincinnati - Division of Human Genetics

Cincinnati, OH 45221-0389
United States

Louis Muglia

University of Cincinnati - Division of Human Genetics

Cincinnati, OH 45221-0389
United States

Sushil K. Mahata

Government of the United States of America - Veterans Affairs San Diego Healthcare System

San Diego, CA 92161
United States

University of California, San Diego (UCSD) - Department of Medicine

9500 Gilman Drive
La Jolla, CA 92093
United States

Scott O'Grady

University of Minnesota - St. Paul - Department of Animal Science

1364 Eckles Avenue
St Paul, MI
United States

Leslie Baier

National Institutes of Health - Phoenix Epidemiology and Clinical Research Branch

4212 N 16th Street
Phoenix, AZ 85016
United States

Yuk Y. Sham

University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology

Jackson Hall 6-125
321 Church St. SE
Minneapolis, MN 55455
United States

Alessandro Bartolomucci (Contact Author)

University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology ( email )

Jackson Hall 6-125
321 Church St. SE
Minneapolis, MN 55455
United States

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