Control of Adhesion GPCR Function Through Proteolytic Processing

Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 234)

Graphical Abstract

Proteolytic processing events in adhesion GPCRs. aGPCRs can undergo multiple autoproteolytic (red asterisks) and proteolytic processing events by exogenous proteases (yellow asterisks) that may be involved in signaling events of the receptors.

Abstract

Proteolytic processing is an unusual property of adhesion family G protein-coupled receptors (aGPCRs) that was observed upon their cloning and biochemical characterization.Ever since, much effort has been dedicated to delineate the mechanisms and requirements for cleavage events in the control of aGPCR function. Most notably, all aGPCRs possess a juxtamembrane protein fold, the GPCR autoproteolysis-inducing (GAIN) domain, which operates as an autoprotease for many aGPCR homologs investigated thus far. Analysis of its autoproteolytic reaction, the consequences for receptor fate and function, and the allocation of physiological effects to this peculiar feature of aGPCRs has occupied the experimental agenda of the aGPCR field and shaped our current understanding of the signaling properties and cell biological effects of aGPCRs. Interestingly, individual aGPCRs may undergo additional proteolytic steps, one of them resulting in shedding of the entire ectodomain that is secreted and can function independently. Here, we summarize the current state of knowledge on GAIN domain-mediated and GAIN domain-independent aGPCR cleavage events and their significance for the pharmacological and cellular actions of aGPCRs. Further, we compare and contrast the proteolytic profile of aGPCRs with known signaling routes that are governed through proteolysis of surface molecules such as the Notch and ephrin pathways.

Keywords

Adhesion GPCR GAIN domain GPS Proteolysis Autoproteolysis 

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Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  • Matthias Nieberler
    • 1
  • Robert J. Kittel
    • 1
  • Alexander G. Petrenko
    • 2
  • Hsi-Hsien Lin
    • 3
    • 4
  • Tobias Langenhan
    • 1
  1. 1.Department of NeurophysiologyInstitute of Physiology, University of WürzburgWürzburgGermany
  2. 2.Laboratory of Receptor Cell BiologyShemyakin-Ovchinnikov Institute of Bioorganic ChemistryMoscowRussia
  3. 3.Department of Microbiology and ImmunologyCollege of Medicine, Chang Gung UniversityTao-YuanTaiwan
  4. 4.Chang Gung Immunology Consortium and Department of Anatomic PathologyChang Gung Memorial Hospital-LinkouTao-YuanTaiwan

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