The GPS Motif Is a Molecular Switch for Bimodal Activities of Adhesion Class G Protein-Coupled Receptors

• Published in: Cell reports (Cambridge) Vol. 2; no. 2; pp. 321 - 331
• Main Authors: Prömel, Simone, Frickenhaus, Marie, Hughes, Samantha, Mestek, Lamia, Staunton, David, Woollard, Alison, Vakonakis, Ioannis, Schöneberg, Torsten, Schnabel, Ralf, Russ, Andreas P., Langenhan, Tobias
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.08.2012; Cell Press; Elsevier
• Subjects: Amino Acid Motifs - physiology; Animals; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins; Indexing in process; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Peptide - genetics; Receptors, Peptide - metabolism; Signal Transduction - physiology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2012.06.015

Adhesion class G protein-coupled receptors (aGPCR) form the second largest group of seven-transmembrane-spanning (7TM) receptors whose molecular layout and function differ from canonical 7TM receptors. Despite their essential roles in immunity, tumorigenesis, and development, the mechanisms of aGPCR activation and signal transduction have remained obscure to date. Here, we use a transgenic assay to define the protein domains required in vivo for the activity of the prototypical aGPCR LAT-1/Latrophilin in Caenorhabditis elegans. We show that the GPCR proteolytic site (GPS) motif, the molecular hallmark feature of the entire aGPCR class, is essential for LAT-1 signaling serving in two different activity modes of the receptor. Surprisingly, neither mode requires cleavage but presence of the GPS, which relays interactions with at least two different partners. Our work thus uncovers the versatile nature of aGPCR activity in molecular detail and places the GPS motif in a central position for diverse protein-protein interactions. [Display omitted] ► The GPS motif of the prototype aGPCR LAT-1 transduces two different signals ► Proteolysis of LAT-1 is not required for receptor activity ► Teneurins are potential coreceptors with latrophilins All adhesion class G protein-coupled receptors (aGPCRs) are marked by the presence of a juxtamembrane GPCR proteolytic site (GPS). Current work by Langenhan and colleagues demonstrates that the GPS motif constitutes a structural interface for differential protein interactions required for development and fertility in C. elegans. The work also suggests that aGPCRs take an unusual route to transduce the signal over membrane: activity ensues by transactivation of homomeric partner receptors. These findings provide new insights into the physiological and molecular intricacy of these enigmatic receptors.