A dynamic charge-charge interaction modulates PP2A:B56 substrate recruitment

Elife. 2020 Mar 20;9:e55966. doi: 10.7554/eLife.55966.


The recruitment of substrates by the ser/thr protein phosphatase 2A (PP2A) is poorly understood, limiting our understanding of PP2A-regulated signaling. Recently, the first PP2A:B56 consensus binding motif, LxxIxE, was identified. However, most validated LxxIxE motifs bind PP2A:B56 with micromolar affinities, suggesting that additional motifs exist to enhance PP2A:B56 binding. Here, we report the requirement of a positively charged motif in a subset of PP2A:B56 interactors, including KIF4A, to facilitate B56 binding via dynamic, electrostatic interactions. Using molecular and cellular experiments, we show that a conserved, negatively charged groove on B56 mediates dynamic binding. We also discovered that this positively charged motif, in addition to facilitating KIF4A dephosphorylation, is essential for condensin I binding, a function distinct and exclusive from PP2A-B56 binding. Together, these results reveal how dynamic, charge-charge interactions fine-tune the interactions mediated by specific motifs, providing a new framework for understanding how PP2A regulation drives cellular signaling.

Keywords: E. coli; KIF4A; PP2A-B56; biochemistry; chemical biology; dynamic, charge-charge interactions; human; intrinsically disordered protein; molecular biophysics; protein phosphatase; structural and cell biology; structural biology.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Cloning, Molecular
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Kinesins / genetics
  • Kinesins / metabolism
  • Models, Molecular
  • Mutation
  • Protein Conformation
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism*
  • RNA Interference
  • Substrate Specificity


  • PPP2R5C protein, human
  • Protein Phosphatase 2
  • KIF4A protein, human
  • Kinesins

Associated data

  • PDB/6OYL
  • PDB/6VRO