N-terminal fragment shedding contributes to signaling of the full-length adhesion receptor ADGRL3.

ABSTRACT: Most adhesion G protein-coupled receptors (GPCRs) undergo autoproteolytic cleavage during receptor biosynthesis, resulting in noncovalently bound N-terminal fragments (NTFs) and C-terminal fragments (CTFs) that remain associated during receptor trafficking to the plasma membrane. While substantial evidence supports increased G protein signaling when just the CTF is expressed, there is an ongoing debate about whether NTF removal is required to initiate signaling in the context of the WT receptor. Here, we use adhesion GPCR latrophilin-3 (ADGRL3) as a model receptor to investigate tethered agonist (TA)-mediated activation. First, we show that extending the N terminus of the TA in ADGRL3 CTF disrupts G protein signaling. This suggests that if the TA is not fully exposed, it is unlikely to int

SUBMITTER: Perry-Hauser NA 

PROVIDER: S-EPMC11849108 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature