期刊
MOLECULAR CELL
卷 31, 期 6, 页码 873-885出版社
CELL PRESS
DOI: 10.1016/j.molcel.2008.08.006
关键词
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资金
- NCI NIH HHS [R01 CA123155-01A1, R01 CA123155-03, R01 CA123155-04, R01 CA123155-02, R01 CA123155, CA123155] Funding Source: Medline
- NIBIB NIH HHS [P30 EB009998] Funding Source: Medline
Protein phosphatase 2A (PP2A) regulates many essential aspects of cellular physiology. Members of the regulatory B/B55/PR55 family are thought to play a key role in the dephosphorylation of Tau, whose hyperphosphorylation contributes to Alzheimer's disease. The underlying mechanisms of the PP2A-Tau connection remain largely enigmatic. Here, we report the complete reconstitution of a Tau dephosphorylation assay and the crystal structure of a heterotrimeric PP2A holoenzyme involving the regulatory subunit B alpha. We show that B alpha specifically and markedly facilitates dephosphorylation of the phosphorylated Tau in our reconstituted assay. The B alpha subunit comprises a seven-bladed beta propeller, with an acidic, substrate-binding groove located in the center of the propeller. The beta propeller latches onto the ridge of the PP2A scaffold subunit with the help of a protruding beta hairpin arm. Structure-guided mutagenesis studies revealed the underpinnings of PP2A-mediated dephosphorylation of Tau.
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