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Monoubiquitination promotes calpain cleavage of the protein phosphatase 2A (PP2A) regulatory subunit ?4, altering PP2A stability and microtubule-associated protein phosphorylation.


ABSTRACT: 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. ?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 ?4 triggers calpain-mediated cleavage and switches ?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 ?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 ?4, and dysregulation of ?4 cleavage may contribute to Opitz syndrome and Alzheimer disease.

SUBMITTER: Watkins GR 

PROVIDER: S-EPMC3397847 | biostudies-other | 2012 Jul

REPOSITORIES: biostudies-other

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Monoubiquitination promotes calpain cleavage of the protein phosphatase 2A (PP2A) regulatory subunit α4, altering PP2A stability and microtubule-associated protein phosphorylation.

Watkins Guy R GR   Wang Ning N   Mazalouskas Matthew D MD   Gomez Rey J RJ   Guthrie Chris R CR   Kraemer Brian C BC   Schweiger Susann S   Spiller Benjamin W BW   Wadzinski Brian E BE  

The Journal of biological chemistry 20120521 29


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. α4 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 α4 triggers calpain-mediated cleavag  ...[more]

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