期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 29, 页码 24207-24215出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.368613
关键词
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资金
- National Institutes of Health [DK070787, GM051366, NS064131, T32 GM07628]
- American Cancer Society [IRG-58-009-49]
- Department of Veterans Affairs Merit Review Grant [114891]
- Ataxia UK
- Tenovus Scotland
Multiple neurodegenerative disorders are linked to aberrant phosphorylation of microtubule-associated proteins (MAPs). Protein phosphatase 2A (PP2A) is the major MAP phosphatase; however, little is known about its regulation at microtubules. alpha 4 binds the PP2A catalytic subunit (PP2Ac) and the microtubule-associated E3 ubiquitin ligase MID1, and through unknown mechanisms can both reduce and enhance PP2Ac stability. We show MID1-dependent monoubiquitination of alpha 4 triggers calpain-mediated cleavage and switches alpha 4's activity from protective to destructive, resulting in increased Tau phosphorylation. This regulatory mechanism appears important in MAP-dependent pathologies as levels of cleaved alpha 4 are decreased in Opitz syndrome and increased in Alzheimer disease, disorders characterized by MAP hypophosphorylation and hyperphosphorylation, respectively. These findings indicate that regulated inter-domain cleavage controls the dual functions of alpha 4, and dysregulation of alpha 4 cleavage may contribute to Opitz syndrome and Alzheimer disease.
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