The Parkinson's-disease-associated receptor GPR37 undergoes metalloproteinase-mediated N-terminal cleavage and ectodomain shedding
| Autor: | Jussi T. Tuusa, S. Orvokki Mattila, Ulla E. Petäjä-Repo |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Proteolysis Biology Cell Line Receptors G-Protein-Coupled 03 medical and health sciences medicine Humans Receptor Secretory pathway G protein-coupled receptor medicine.diagnostic_test Endoplasmic reticulum HEK 293 cells Membrane Proteins Parkinson Disease Cell Biology Dipeptides Molecular biology Cell biology Protein Structure Tertiary 030104 developmental biology HEK293 Cells Ectodomain Cell culture Metalloproteases |
| Zdroj: | Journal of cell science. 129(7) |
| ISSN: | 1477-9137 |
| Popis: | The G-protein-coupled receptor 37 ( GPR37) has been implicated in the juvenile form of Parkinson's disease, in dopamine signalling and in the survival of dopaminergic cells in animal models. The structure and function of the receptor, however, have remained enigmatic. Here, we demonstrate that although GPR37 matures and is exported from the endoplasmic reticulum in a normal manner upon heterologous expression in HEK293 and SH-SY5Y cells, its long extracellular N-terminus is subject to metalloproteinase-mediated limited proteolysis between E167 and Q168. The proteolytic processing is a rapid and efficient process that occurs constitutively. Moreover, the GPR37 ectodomain is released from cells by shedding, a phenomenon rarely described for GPCRs. Immunofluorescence microscopy further established that although full-length receptors are present in the secretory pathway until the trans-Golgi network, GPR37 is expressed at the cell surface predominantly in the N-terminally truncated form. This notion was verified by flow cytometry and cell surface biotinylation assays. These new findings on the GPR37 N-terminal limited proteolysis may help us to understand the role of this GPCR in the pathophysiology of Parkinson's disease and in neuronal function in general. |
| Databáze: | OpenAIRE |
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