{"doi":"10.17615/7s7n-b848","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 (GPCR) Complement-3a-Receptor1 (C3aR1). So far, the mechanisms of TLQP-21-induced receptor activation remained 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. Interestingly, 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.","journal":"UNC Libraries","year":2020,"id":138883,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9632,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":406230,"name":"Lucy Vulchanova","orcid":"0000-0002-6577-4467","position":1,"is_corresponding":false},{"id":109252,"name":"Alessandro Bartolomucci","orcid":"0000-0001-6439-8829","position":2,"is_corresponding":false},{"id":504646,"name":"Maria F. Sassano","orcid":"0000-0003-1243-2962","position":3,"is_corresponding":false},{"id":600963,"name":"Cinzia Severini","orcid":"0000-0002-6932-704X","position":4,"is_corresponding":false},{"id":266886,"name":"Raffaello Verardi","orcid":"0000-0002-2613-1223","position":5,"is_corresponding":false},{"id":601550,"name":"Vitaly V. Vostrikov","orcid":null,"position":6,"is_corresponding":false},{"id":601551,"name":"Patrick D. Braun","orcid":null,"position":7,"is_corresponding":false},{"id":601552,"name":"Allison Gurney","orcid":null,"position":8,"is_corresponding":false},{"id":75533,"name":"Cheryl Cero","orcid":"0000-0003-0513-8669","position":9,"is_corresponding":false},{"id":409123,"name":"Tata Gopinath","orcid":"0000-0002-5237-2135","position":10,"is_corresponding":false},{"id":225473,"name":"Bryan L. Roth","orcid":"0000-0002-0561-6520","position":11,"is_corresponding":false},{"id":364784,"name":"Gianluigi Veglia","orcid":"0000-0002-2795-6964","position":12,"is_corresponding":false},{"id":601549,"name":"Roberta Possenti","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:17:06.651725Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}