Format

Send to

Choose Destination
Structure. 2014 Dec 2;22(12):1744-1753. doi: 10.1016/j.str.2014.10.001. Epub 2014 Nov 13.

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

Author information

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: vegli001@umn.edu.
9
Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: abartolo@umn.edu.

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.

PMID:
25456411
PMCID:
PMC4353613
DOI:
10.1016/j.str.2014.10.001
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center