Selective proteasomal degradation of the B'β subunit of protein phosphatase 2A by the E3 ubiquitin ligase adaptor Kelch-like 15

J Biol Chem. 2012 Dec 21;287(52):43378-89. doi: 10.1074/jbc.M112.420281. Epub 2012 Nov 7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation, Enzymologic / physiology
  • HEK293 Cells
  • Holoenzymes / genetics
  • Holoenzymes / metabolism
  • Humans
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Multimerization / physiology*
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism*
  • Proteolysis*


  • CUL3 protein, human
  • Cullin Proteins
  • Holoenzymes
  • KLHL15 protein, human
  • Microfilament Proteins
  • Protein Phosphatase 2
  • Proteasome Endopeptidase Complex