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

Cheryl Cero; Vitaly V. Vostrikov; Raffaello Verardi; Cinzia Severini; Tata Gopinath; Patrick D. Braun; Maria F. Sassano; Allison Gurney; Bryan L. Roth; Lucy Vulchanova; Roberta Possenti; Gianluigi Veglia; Alessandro Bartolomucci

doi:10.1016/j.str.2014.10.001

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

Cheryl Cero, Vitaly V. Vostrikov, Raffaello Verardi, Cinzia Severini, Tata Gopinath, Patrick D. Braun, Maria F. Sassano, Allison Gurney, Bryan L. Roth, Lucy Vulchanova, Roberta Possenti, Gianluigi Veglia, Alessandro Bartolomucci

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1744-1753
Number of pages	10
Journal	Structure
Volume	22
Issue number	12
DOIs	https://doi.org/10.1016/j.str.2014.10.001
State	Published - Dec 2 2014

Bibliographical note

Funding Information:
Supported by the Minnesota Partnership for Biotechnology and Medical Genomic, Decade of Discovery in Diabetes Grant (to A.B.), NIH/DK102496 (to A.B.), NIH R01DE021996 and NIH R21DA025170 (to L.V.), and the NIMH Psychoactive Drug Screening Program (to B.L.R. and M.F.S.). NMR experiments were carried out at the Minnesota NMR Center. 3T3L1 cells were provided by The Molecular & Cellular Basis of Obesity Core, Minnesota Obesity Center (P30 DK050456). We thank D. Piomelli, G. Bottegoni, W. Rocchia, A. Lodola, and M. Mor for important suggestions in various stages of the study, and I. Ninkovich, P. Petrocchi, and M. Razzoli for technical help.

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© 2014 Elsevier Ltd. All rights reserved.

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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.",

author = "Cheryl Cero and Vostrikov, {Vitaly V.} and Raffaello Verardi and Cinzia Severini and Tata Gopinath and Braun, {Patrick D.} and Sassano, {Maria F.} and Allison Gurney and Roth, {Bryan L.} and Lucy Vulchanova and Roberta Possenti and Gianluigi Veglia and Alessandro Bartolomucci",

note = "Funding Information: Supported by the Minnesota Partnership for Biotechnology and Medical Genomic, Decade of Discovery in Diabetes Grant (to A.B.), NIH/DK102496 (to A.B.), NIH R01DE021996 and NIH R21DA025170 (to L.V.), and the NIMH Psychoactive Drug Screening Program (to B.L.R. and M.F.S.). NMR experiments were carried out at the Minnesota NMR Center. 3T3L1 cells were provided by The Molecular & Cellular Basis of Obesity Core, Minnesota Obesity Center (P30 DK050456). We thank D. Piomelli, G. Bottegoni, W. Rocchia, A. Lodola, and M. Mor for important suggestions in various stages of the study, and I. Ninkovich, P. Petrocchi, and M. Razzoli for technical help. Publisher Copyright: {\textcopyright} 2014 Elsevier Ltd. All rights reserved.",

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doi = "10.1016/j.str.2014.10.001",

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T1 - The TLQP-21 peptide activates the G-protein-coupled receptor C3aR1 via a folding-upon-binding mechanism

AU - Cero, Cheryl

AU - Vostrikov, Vitaly V.

AU - Verardi, Raffaello

AU - Severini, Cinzia

AU - Gopinath, Tata

AU - Braun, Patrick D.

AU - Sassano, Maria F.

AU - Gurney, Allison

AU - Roth, Bryan L.

AU - Vulchanova, Lucy

AU - Possenti, Roberta

AU - Veglia, Gianluigi

AU - Bartolomucci, Alessandro

N1 - Funding Information: Supported by the Minnesota Partnership for Biotechnology and Medical Genomic, Decade of Discovery in Diabetes Grant (to A.B.), NIH/DK102496 (to A.B.), NIH R01DE021996 and NIH R21DA025170 (to L.V.), and the NIMH Psychoactive Drug Screening Program (to B.L.R. and M.F.S.). NMR experiments were carried out at the Minnesota NMR Center. 3T3L1 cells were provided by The Molecular & Cellular Basis of Obesity Core, Minnesota Obesity Center (P30 DK050456). We thank D. Piomelli, G. Bottegoni, W. Rocchia, A. Lodola, and M. Mor for important suggestions in various stages of the study, and I. Ninkovich, P. Petrocchi, and M. Razzoli for technical help. Publisher Copyright: © 2014 Elsevier Ltd. All rights reserved.

PY - 2014/12/2

Y1 - 2014/12/2

N2 - 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.

AB - 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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JO - Structure

JF - Structure

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ER -

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

Abstract

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