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.

Cero, C., Vostrikov, V., Verardi, R., Severini, C., Gopinath, T., Braun, P., et al. (2014). The TLQP-21 Peptide Activates the G-Protein-Coupled Receptor C3aR1 via a Folding-upon-Binding Mechanism. STRUCTURE, 22(12), 1744-1753 [10.1016/j.str.2014.10.001].

The TLQP-21 Peptide Activates the G-Protein-Coupled Receptor C3aR1 via a Folding-upon-Binding Mechanism.

POSSENTI, ROBERTA;
2014-12-01

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.
dic-2014
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/09 - FISIOLOGIA
English
Con Impact Factor ISI
Cero, C., Vostrikov, V., Verardi, R., Severini, C., Gopinath, T., Braun, P., et al. (2014). The TLQP-21 Peptide Activates the G-Protein-Coupled Receptor C3aR1 via a Folding-upon-Binding Mechanism. STRUCTURE, 22(12), 1744-1753 [10.1016/j.str.2014.10.001].
Cero, C; Vostrikov, V; Verardi, R; Severini, C; Gopinath, T; Braun, P; Sassano, M; Gurney, A; Roth, B; Vulchanova, L; Possenti, R; Veglia, G; Bartolomucci, A
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/101288
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