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

Abstract

SUMMARY 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.

The neuropeptide TLQP-21 opposes obesity via C3aR1-mediated enhancement of adrenergic-induced lipolysis

“…After 9 weeks on HFD, the obese mice were individually housed for baseline recording of body weight, food intake, and body composition. Afterwards, mice were randomized to receive peptide (TLQP-21 [12] or R21A [14] 5 mg/kg/d) or saline daily via i.p. injection (the dose was chosen based on published results [13], [17] and a preliminary dose–response experiment (data not shown)).…”

“…Here we identified a novel lipolytic and anti-obesity mechanism exerted by TLQP-21, a neuropeptide encoded by the pro-peptide VGF (non-acronymic), that targets primarily the complement 3a receptor 1 (C3aR1) on the adipocyte membrane [12], [13], [14], [15]. TLQP-21 is expressed in the central nervous system and peripheral nervous system, including sympathetic nerve terminal in the adipose tissue [12], [13], [16].…”

Is the Complement Activation Product C3a a Proinflammatory Molecule? Re-evaluating the Evidence and the Myth

“…Studies in this area were perhaps the first reports of functional antagonism between C3a and C5a at the molecular level. Until recently, C3a was thought to be the only ligand for C3aR; however, the neuropeptide TLQP-21, a cleavage fragment of the VGL propeptide, was shown to bind and activate murine C3aR through conformational change of the ligand upon receptor binding (25,26).…”

The Pathways Involved in TLQP-62 Mediated Biological Functions

“…However, these peptides ligates to a yet to be identified receptor(s). In previous study it has been described that TLQP-21 ligates to the C3a receptor [31,32]. The C3a and TLQP-21 with an intact C-terminal Ala-Arg moiety activated the C3aR1 that was not present in TLQP-62.…”

“…Till now three receptors of TLQP-21 have been identified by using powerful proteomic methods: HSPA8 [39,40], C3AR1 [32], and gC1qR [41,42]. Among these receptors, C3AR1 and gC1qR are receptor were of rodent model, on the contrary, upto now HSPA8 is a receptor (first putative) for human model [32,39,40,42].…”