A Comprehensive Mutagenesis Screen of the Adhesion GPCR Latrophilin-1/ADGRL1
| Autor: | Jana Winkler, Hannah M. Stoveken, Gregory G. Tall, Katherine Leon, Katarzyna Merdas, Pradnya Narkhede, Amanuel Kibrom, Simone Prömel, Yue Lu, Demet Araç, Olha V. Nazarko, Gabriel S. Salzman |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Mutation Multidisciplinary Mutagenesis (molecular biology technique) Biology medicine.disease_cause Phenotype Cell biology 03 medical and health sciences Latrophilin 1 Transmembrane domain 030104 developmental biology Drug development medicine lcsh:Q lcsh:Science Receptor G protein-coupled receptor |
| Zdroj: | iScience, Vol 3, Iss, Pp 264-278 (2018) |
| ISSN: | 2589-0042 |
| DOI: | 10.1016/j.isci.2018.04.019 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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