The TLQP-21 peptide activates the G-protein-coupled receptor C3aR1 via a folding-upon-binding mechanism. Structure 2014 Dec 02;22(12):1744-1753
Date
12/03/2014Pubmed ID
25456411Pubmed Central ID
PMC4353613DOI
10.1016/j.str.2014.10.001Scopus ID
2-s2.0-84914156029 (requires institutional sign-in at Scopus site) 49 CitationsAbstract
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 List
Cero C, Vostrikov VV, Verardi R, Severini C, Gopinath T, Braun PD, Sassano MF, Gurney A, Roth BL, Vulchanova L, Possenti R, Veglia G, Bartolomucci AAuthor
Gopinath Tata PhD Assistant Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdipocytesAnimals
Female
Mice
Models, Molecular
Peptide Fragments
Protein Binding
Protein Conformation
Rats
Rats, Wistar
Receptors, Complement
Spleen
