title: The TLQP-21 peptide activates the G-protein-coupled receptor C3aR1 via a folding-upon-binding mechanism.
abstract: TLQP-21, a VGF-encoded peptide is emerging as a novel target for obesity-associated disorders. TLQP-21 is found in the sympathetic nerve terminals in the adipose tissue and targets the G-protein-coupled receptor complement-3a receptor1 (C3aR1). The mechanisms of TLQP-21-induced receptor activation remain unexplored. Here, we report that TLQP-21 is intrinsically disordered and undergoes a disorder-to-order transition, adopting an α-helical conformation upon targeting cells expressing the C3aR1. We determined that the hot spots for TLQP-21 are located at the C terminus, with mutations in the last four amino acids progressively reducing the bioactivity and, a single site mutation (R21A) or C-terminal amidation abolishing its function completely. Additionally, the human TLQP-21 sequence carrying a S20A substitution activates the human C3aR1 receptor with lower potency compared to the rodent sequence. These studies reveal the mechanism of action of TLQP-21 and provide molecular templates for designing agonists and antagonists to modulate C3aR1 functions.
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Cero
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Vitaly V
authors.initials: VV
authors.lastname: Vostrikov
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Raffaello
authors.initials: R
authors.lastname: Verardi
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, 00143 Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Severini
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Tata
authors.initials: T
authors.lastname: Gopinath
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Braun
authors.affiliation: Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Sassano
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Gurney
authors.affiliation: Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Lucy
authors.initials: L
authors.lastname: Vulchanova
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, 00143 Rome, Italy; Department of Medicine of System, University of Rome "Tor Vergata", 00133 Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Possenti
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: vegli001@umn.edu.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Veglia
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: abartolo@umn.edu.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bartolomucci
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000818:Animals; D005260:Female; D051379:Mice; D008958:Models, Molecular; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D011951:Receptors, Complement / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; D011951:Receptors, Complement; C522412:TLQP-21 peptide; C085567:complement C3a receptor