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Biased Signaling is Structurally Encoded As An Autoproteolysis Event in Adhesion G Protein-Coupled Receptor Latrophilin-3/ADGRL3
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  • Estefania Ojeda-Muñiz,
  • Brenda Rodríguez-Hernández,
  • Petra Segura-Landa,
  • Kerlys Correoso-Braña,
  • Antony Boucard
Estefania Ojeda-Muñiz
Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional
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Brenda Rodríguez-Hernández
Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional
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Petra Segura-Landa
Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional
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Kerlys Correoso-Braña
Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional
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Antony Boucard
Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional

Corresponding Author:[email protected]

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Abstract

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 Gi2 and G12/13. These data unveil the underpinnings of biased signaling for aGPCRs defined by GPS autoproteolysis.
17 Jan 2023Submitted to Basic & Clinical Pharmacology & Toxicology
18 Jan 2023Assigned to Editor
18 Jan 2023Submission Checks Completed
18 Jan 2023Review(s) Completed, Editorial Evaluation Pending
19 Jan 2023Reviewer(s) Assigned
22 Feb 2023Editorial Decision: Revise Major
20 May 20231st Revision Received
23 May 2023Assigned to Editor
23 May 2023Submission Checks Completed
23 May 2023Review(s) Completed, Editorial Evaluation Pending
23 May 2023Reviewer(s) Assigned
15 Jun 2023Editorial Decision: Revise Minor
05 Jul 20232nd Revision Received
05 Jul 2023Assigned to Editor
05 Jul 2023Submission Checks Completed
05 Jul 2023Review(s) Completed, Editorial Evaluation Pending
06 Jul 2023Editorial Decision: Accept