Tethered agonist exposure in intact adhesion/class B2 GPCRs through intrinsic structural flexibility of the GAIN domain

摘要: Adhesion G protein-coupled receptors (aGPCRs)/family B2 GPCRs execute critical tasks during development and the operation of organs, their genetic lesions are associated with human disorders, including cancers. Exceptional structural aGPCR features presence a tethered agonist (TA) concealed within GPCR autoproteolysis-inducing (GAIN) domain non-covalent heteromeric two-subunit layout. How TA is poised for activation while maintaining this delicate receptor architecture central to conflicting signaling paradigms that either involve or exclude heterodimer separation. We investigated matter in five mammalian homologs (ADGRB3, ADGRE2, ADGRE5, ADGRG1, ADGRL1) demonstrate intact heterodimers exist at cell surface, core region becomes unmasked cleaved GAIN domain, intra-GAIN movements regulate level exposure, thereby likely controlling activity. Collectively, these findings delineate unifying mechanism TA-dependent aGPCRs.