The TLQP-21 peptide activates the G-protein-coupled receptor C3aR1 via a folding-upon-binding mechanism

  • Structure. 2014 Dec 2;22(12):1744-1753. doi: 10.1016/j.str.2014.10.001.
Cheryl Cero  1 ,  Vitaly V Vostrikov  2 ,  Raffaello Verardi  2 ,  Cinzia Severini  3 ,  Tata Gopinath  2 ,  Patrick D Braun  4 ,  Maria F Sassano  5 ,  Allison Gurney  1 ,  Bryan L Roth  5 ,  Lucy Vulchanova  6 ,  Roberta Possenti  7 ,  Gianluigi Veglia  8 ,  Alessandro Bartolomucci  9
Affiliations
  • 1. Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA.
  • 2. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
  • 3. Institute of Cell Biology and Neurobiology, National Research Council, 00143 Rome, Italy.
  • 4. Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA.
  • 5. 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.
  • 6. Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
  • 7. 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.
  • 8. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: [email protected].
  • 9. Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: [email protected].
PMID: 25456411 DOI: 10.1016/j.str.2014.10.001
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.

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