Adhesion G protein-coupled receptors (aGPCRs) possess a unique topology
including the presence of a GPCR proteolysis site (GPS) which upon
autoproteolysis generates two functionally distinct fragments that
remain non-covalently associated at the plasma membrane. A proposed
activation mechanism for aGPCRs involves the release of a tethered
agonist which depends on cleavage at the GPS. However, this hypothesis
has been challenged by the observation that non-cleavable aGPCRs exhibit
constitutive activity, thus making the function of GPS cleavage widely
enigmatic. In this study, we sought to elucidate the function of
GPS-mediated cleavage through the study of G protein coupling with
Latrophilin-3/ADGRL3, a prototypical aGPCR involved in synapse formation
and function. Using BRET-based G protein biosensors, we reveal that an
autoproteolysis-deficient mutant of ADGRL3 retains constitutive
activity. Surprisingly, we uncover that cleavage deficiency leads to a
signaling bias directed at potentiating the activity of select G
proteins such as G and G. These
data unveil the underpinnings of biased signaling for aGPCRs defined by
GPS autoproteolysis.
Adhesion G protein‐coupled receptors (aGPCRs) possess a unique topology, including the presence of a GPCR proteolysis site (GPS), which, upon autoproteolysis, generates two functionally distinct fragments that remain non‐covalently associated at the plasma membrane. A proposed activation mechanism for aGPCRs involves the exposure of a tethered agonist, which depends on cleavage at the GPS. However, this hypothesis has been challenged by the observation that non‐cleavable aGPCRs exhibit constitutive activity, thus making the function of GPS cleavage widely enigmatic. In this study, we sought to elucidate the function of GPS‐mediated cleavage through the study of G protein coupling with Latrophilin‐3/ADGRL3, a prototypical aGPCR involved in synapse formation and function. Using BRET‐based G protein biosensors, we reveal that an autoproteolysis‐deficient mutant of ADGRL3 retains constitutive activity. Surprisingly, we uncover that cleavage deficiency leads to a signalling bias directed at potentiating the activity of select G proteins such as Gi2 and G12/13. These data unveil the underpinnings of biased signalling for aGPCRs defined by GPS autoproteolysis.
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