Association between Presenilin-1 and TRAF6 modulates regulated intramembrane proteolysis of the p75NTRneurotrophin receptor
| Autor: | James C. Powell, Justin V. McCarthy, Raunak Jain, Ciara Twomey |
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| Rok vydání: | 2009 |
| Předmět: |
Models
Molecular Proline Proteolysis Glutamic Acid Transfection Receptor Nerve Growth Factor Biochemistry Regulated Intramembrane Proteolysis Presenilin Mice Cellular and Molecular Neuroscience Ubiquitin mental disorders Presenilin-1 medicine Animals Humans Immunoprecipitation Low-affinity nerve growth factor receptor Amino Acid Sequence Receptor Cell Line Transformed TNF Receptor-Associated Factor 6 biology medicine.diagnostic_test Ubiquitination Protein Structure Tertiary Rats nervous system diseases Ubiquitin ligase Cell biology nervous system Mutation biology.protein Cancer research Densitometry Protein Binding Neurotrophin |
| Zdroj: | Journal of Neurochemistry. 108:216-230 |
| ISSN: | 1471-4159 0022-3042 |
| DOI: | 10.1111/j.1471-4159.2008.05763.x |
| Popis: | The p75 neurotrophin receptor (p75(NTR)) is a member of the tumour necrosis factor superfamily, which relies on the recruitment of cytosolic protein partners including the tumour necrosis factor receptor-associated factor 6 (TRAF6) E3 ubiquitin ligase to produce cellular responses. Recently, p75(NTR) was also shown to undergo presenilin-dependent, gamma-secretase-mediated regulated intramembrane proteolysis. In this study, we report the characterization of a highly conserved TRAF6-binding site (PxExxAr/Ac) in presenilin-1 (PS1) that mediates nerve growth factor (NGF)-induced association between PS1 and TRAF6. We demonstrate that disruption of this interaction between PS1 and TRAF6 inhibits TRAF6 autoubiquitination and gamma-secretase cleavage of p75(NTR). Additionally, we show that PS1-deficiency antagonizes NGF-induced I-kappaB degradation. Finally, we also show that p75(NTR) is a substrate for TRAF6-mediated ubiquitination and that TRAF6 E3 ligase activity is required for regulated intramembrane proteolysis of p75(NTR). In summary, our data suggest that an NGF-induced association between PS1 and TRAF6 influences regulated intramembrane proteolysis of p75(NTR). |
| Databáze: | OpenAIRE |
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