Specific and direct modulation of the interaction between adhesion GPCR GPR56/ADGRG1 and tissue transglutaminase 2 using synthetic ligands
| Autor: | Demet Araç, Shohei Koide, Shu Zhang, Gabriel S. Salzman, Celia G. Fernandez |
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| Rok vydání: | 2020 |
| Předmět: |
Insecta
Tissue transglutaminase Biophysics lcsh:Medicine Ligands Biochemistry Article Receptors G-Protein-Coupled Protein Domains Laminin GTP-Binding Proteins Cell Adhesion Animals Humans Protein Glutamine gamma Glutamyltransferase 2 Binding site Receptor lcsh:Science Cells Cultured G protein-coupled receptor Mammals Multidisciplinary Binding Sites Transglutaminases biology Chemistry Drug discovery lcsh:R Ligand (biochemistry) Cell biology GPR56 HEK293 Cells biology.protein lcsh:Q Function (biology) Protein Binding Signal Transduction Neuroscience |
| Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-9 (2020) |
| ISSN: | 2045-2322 |
| Popis: | Blocking the interaction between cell-surface receptors and their ligands is a proven therapeutic strategy. Adhesion G protein-coupled receptors (aGPCRs) are key cell-surface receptors that regulate numerous pathophysiological processes, and their large extracellular regions (ECRs) mediate ligand binding and function. The aGPCR GPR56/ADGRG1 regulates central nervous system myelination and melanoma progression by interacting with its ligand, tissue transglutaminase 2 (TG2), but the molecular basis for this interaction is largely undefined. Here, we show that the C-terminal portion of TG2 directly interacted with the GPR56 ECR with high-nanomolar affinity, and used site-directed mutagenesis to identify a patch of conserved residues on the pentraxin/laminin-neurexin-sex-hormone-binding-globulin-like (PLL) domain of GPR56 as the TG2 binding site. Importantly, we also show that the GPR56-TG2 interaction was blocked by previously-reported synthetic proteins, termed monobodies, that bind the GPR56 ECR in a domain- and species-specific manner. This work provides unique tools to modulate aGPCR-ligand binding and establishes a foundation for the development of aGPCR-targeted therapeutics. |
| Databáze: | OpenAIRE |
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