Regulation and subcellular compartmentalization of ataxin-1 phosphorylation at Serine776.
2011-03
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Regulation and subcellular compartmentalization of ataxin-1 phosphorylation at Serine776.
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2011-03
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Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant cerebellar ataxia caused by the expansion of a CAG repeat encoding an abnormally long polyglutamine tract in Ataxin-1 protein. Although many studies demonstrate that subcellular distribution of Ataxin-1 and protein folding/degradation pathways modulate neurodegeneration, the mechanism of pathogenesis is not completely understood. Phosphorylation of Ataxin-1 at Serine776 (S776) was previously shown to regulate Ataxin-1's functions and SCA1 pathogenicity. In addition, mice expressing human wild type Ataxin-1-[30Q] with a mutation replacing S776 with a phosphomimicking aspartic acid show similar SCA1 pathology as Ataxin-1-[82Q] mice. Here I investigated the mechanism by which phosphorylation of Ataxin-1 at S776 is regulated. I found in the cerebellum a large proportion of Ataxin-1 is phosphorylated at S776 with phosphorylated S776 enriched in the nucleus. While the kinase activity for Ataxin-1 at S776 is localized to the cerebellar cytoplasm, the phosphatase activity is restricted to the nucleus. PP2A was shown to be the phosphatase for phosphorylated S776 Ataxin-1 (Ataxin-1-pS776). 14-3-3, a protein enriched in the cytoplasm, blocks dephosphorylation of Ataxin-1-pS776 by PP2A in the cytoplasm and may affect the shuttling of Ataxin-1 to the nucleus. This work suggests that Ataxin-1 after it is phosphorylated in the cytoplasm, shuttles to the nucleus where it is dephosphorylated by PP2A. The separation of phosphorylation and dephosphorylation of S776-Ataxin-1 into two subcellular compartments may suggest that they regulate different Ataxin-1 functions in different subcellular compartments.
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University of Minnesota Ph.D. dissertation. March 2011. Major: Biochemistry, Molecular Bio, and Biophysics. Advisor: Harry T. Orr. 1 computer file (PDF); xi, 98 pages.
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Lai, Shaojuan. (2011). Regulation and subcellular compartmentalization of ataxin-1 phosphorylation at Serine776.. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/104588.
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