ER residency of the ceramide phosphoethanolamine synthase SMSr relies on homotypic oligomerization mediated by its SAM domain
| Autor: | Andreas Bickert, Matthijs Kol, Sergei Korneev, Joost C. M. Holthuis, Angelika Hilderink, John G. Mina, Birol Cabukusta, Laura Kneller |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Ceramide Multidisciplinary Lipid signaling Golgi apparatus Article Cell biology 03 medical and health sciences symbols.namesake chemistry.chemical_compound 030104 developmental biology Enzyme chemistry Membrane protein Apoptosis symbols Ceramide phosphoethanolamine synthase Diacylglycerol kinase |
| Zdroj: | Scientific Reports Scientific reports, 2017, Vol.7, pp.41290 [Peer Reviewed Journal] |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep41290 |
| Popis: | SMSr/SAMD8 is an ER-resident ceramide phosphoethanolamine synthase with a critical role in controlling ER ceramides and suppressing ceramide-induced apoptosis in cultured cells. SMSr-mediated ceramide homeostasis relies on the enzyme’s catalytic activity as well as on its N-terminal sterile α-motif or SAM domain. Here we report that SMSr-SAM is structurally and functionally related to the SAM domain of diacylglycerol kinase DGKδ, a central regulator of lipid signaling at the plasma membrane. Native gel electrophoresis indicates that both SAM domains form homotypic oligomers. Chemical crosslinking studies show that SMSr self-associates into ER-resident trimers and hexamers that resemble the helical oligomers formed by DGKδ-SAM. Residues critical for DGKδ-SAM oligomerization are conserved in SMSr-SAM and their substitution causes a dissociation of SMSr oligomers as well as a partial redistribution of the enzyme to the Golgi. Conversely, treatment of cells with curcumin, a drug disrupting ceramide and Ca2+ homeostasis in the ER, stabilizes SMSr oligomers and promotes retention of the enzyme in the ER. Our data provide first demonstration of a multi-pass membrane protein that undergoes homotypic oligomerization via its SAM domain and indicate that SAM-mediated self-assembly of SMSr is required for efficient retention of the enzyme in the ER. |
| Databáze: | OpenAIRE |
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