The TRY‐motif in the Relaxin Family Peptide Receptor 3 (RXFP3) functions as a Molecular Switch Between DNA Damage Response and Cell Cycle Control

Abstract

The majority of Rhodopsin‐like Class A G protein‐coupled receptors (GPCRs) contain the conserved Aspartate–Arginine–Tyrosine (DRY) motif in transmembrane helix 3 (TM3). This DRY‐motif is responsible for the presence of an ionic lock, consisting of a salt bridge between the positively charged R3.50 in TM3 and the negatively charged glutamic acid (E6.30) on TM6 in typical rhodopsin‐like GPCRs. While the R3.50 is 96% conserved across all class A GPCRs, D3.49 and Y3.51 are 66, and 67% conserved respectively. This variance in D3.49 and Y3.51 residues potential identifies a locus for evolutionary modification of GPCR signaling. The relaxin family peptide receptor 3 (RXFP3), a Class A GPCR, which plays a crucial role in the aging process via providing resilience to stress, possesses a natural variant of the DRY motif, where Aspartate is replaced by Threonine, creating a TRY motif. This variation enhances the ligand‐independent activity of the RXFP3 receptor. We investigated how this natural variation may be implicated in its stress‐resistance role through selective mutation of the TRY motif back to a canonical DRY sequence. Using an unbiased quantitative proteomic perturbation response approach, we found that protein network analysis revealed that DNA damage repair functions are supported by the presence of a TRY motif while reversion to a DRY sequence in the RXFP3 diverts signaling activity instead to cell‐cycle/cellular senescence control. Thus it is likely that the RXFP3 has been naturally mutated to a TRY sequence to promote its anti‐aging stress sensor role.