Journal article
Selective Proteasomal Degradation of the B′β Subunit of Protein Phosphatase 2A by the E3 Ubiquitin Ligase Adaptor Kelch-like 15
The Journal of biological chemistry, Vol.287(52), pp.43378-43389
12/21/2012
DOI: 10.1074/jbc.M112.420281
PMCID: PMC3527925
PMID: 23135275
Abstract
Background:
Proteasomal degradation of PP2A regulatory subunits has been described, but responsible E3 ubiquitin ligases have remained elusive.
Results:
KLHL15 is an E3 ubiquitin ligase adaptor targeting the B′/B56β regulatory subunit for proteasomal degradation, promoting formation of alternative PP2A holoenzymes.
Conclusion:
KLHL15 contributes to brain-specific expression of B′β and modifies PP2A holoenzyme composition.
Significance:
E3 ligase-mediated B subunit degradation is a novel mechanism to remodel the PP2A heterotrimer.
Protein phosphatase 2A (PP2A), a ubiquitous and pleiotropic regulator of intracellular signaling, is composed of a core dimer (AC) bound to a variable (B) regulatory subunit. PP2A is an enzyme family of dozens of heterotrimers with different subcellular locations and cellular substrates dictated by the B subunit. B′β is a brain-specific PP2A regulatory subunit that mediates dephosphorylation of Ca
2+
/calmodulin-dependent protein kinase II and tyrosine hydroxylase. Unbiased proteomic screens for B′β interactors identified Cullin3 (Cul3), a scaffolding component of E3 ubiquitin ligase complexes, and the previously uncharacterized Kelch-like 15 (KLHL15). KLHL15 is one of ∼40 Kelch-like proteins, many of which have been identified as adaptors for the recruitment of substrates to Cul3-based E3 ubiquitin ligases. Here, we report that KLHL15-Cul3 specifically targets B′β to promote turnover of the PP2A subunit by ubiquitylation and proteasomal degradation. Comparison of KLHL15 and B′β tissue expression profiles suggests that the E3 ligase adaptor contributes to selective expression of the PP2A/B′β holoenzyme in the brain. We mapped KLHL15 residues critical for homodimerization as well as interaction with Cul3 and B′β. Explaining PP2A subunit selectivity, the divergent N terminus of B′β was found necessary and sufficient for KLHL15-mediated degradation, with Tyr-52 having an obligatory role. Although KLHL15 can interact with the PP2A/B′β heterotrimer, it only degrades B′β, thus promoting exchange with other regulatory subunits. E3 ligase adaptor-mediated control of PP2A holoenzyme composition thereby adds another layer of regulation to cellular dephosphorylation events.
Details
- Title: Subtitle
- Selective Proteasomal Degradation of the B′β Subunit of Protein Phosphatase 2A by the E3 Ubiquitin Ligase Adaptor Kelch-like 15
- Creators
- Elizabeth A Oberg - From theShanna K Nifoussi - From theAnne-Claude Gingras - Samuel Lunenfeld Institute, University of Toronto, Toronto, Ontario M5G 1X5, CanadaStefan Strack - From the
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.287(52), pp.43378-43389
- DOI
- 10.1074/jbc.M112.420281
- PMID
- 23135275
- PMCID
- PMC3527925
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
- Grant note
- NS043254; NS056244; NS057714 / National Institutes of Health
- Alternative title
- KLHL15 Down-regulates PP2A/B′β
- Language
- English
- Date published
- 12/21/2012
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984040476102771
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