iScience (May 2018)

A Comprehensive Mutagenesis Screen of the Adhesion GPCR Latrophilin-1/ADGRL1

  • Olha Nazarko,
  • Amanuel Kibrom,
  • Jana Winkler,
  • Katherine Leon,
  • Hannah Stoveken,
  • Gabriel Salzman,
  • Katarzyna Merdas,
  • Yue Lu,
  • Pradnya Narkhede,
  • Gregory Tall,
  • Simone Prömel,
  • Demet Araç

Journal volume & issue
Vol. 3
pp. 264 – 278

Abstract

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Summary: Adhesion G-protein-coupled receptors (aGPCRs) play critical roles in diverse cellular processes in neurobiology, development, immunity, and numerous diseases. The lack of molecular understanding of their activation mechanisms, especially with regard to the transmembrane domains, hampers further studies to facilitate aGPCR-targeted drug development. Latrophilin-1/ADGRL1 is a model aGPCR that regulates synapse formation and embryogenesis, and its mutations are associated with cancer and attention-deficit/hyperactivity disorder. Here, we established functional assays to monitor latrophilin-1 function and showed the activation of latrophilin-1 by its endogenous agonist peptide. Via a comprehensive mutagenesis screen, we identified transmembrane domain residues essential for latrophilin-1 basal activity and for agonist peptide response. Strikingly, a cancer-associated mutation exhibited increased basal activity and failed to rescue the embryonic developmental phenotype in transgenic worms. These results provide a mechanistic foundation for future aGPCR-targeted drug design. : Molecular Biology; Membrane Architecture; Protein Structure Aspects Subject Areas: Molecular Biology, Membrane Architecture, Protein Structure Aspects