Protein polyphosphorylation of lysine residues by inorganic polyphosphate

Mol Cell. 2015 Apr 2;58(1):71-82. doi: 10.1016/j.molcel.2015.02.010. Epub 2015 Mar 12.


The complexity of higher organisms is not simply a reflection of the number of genes. A network of additional regulatory features, including protein post-translational modifications (PTMs), provides functional complexity otherwise inaccessible to a single gene product. Virtually all proteins are targets of PTMs. Here we characterize "polyphosphorylation" as the covalent attachment of inorganic polyphosphate (polyP) to target proteins. We found that nuclear signal recognition 1 (Nsr1) and its interacting partner, topoisomerase 1 (Top1), are polyphosphorylated. This modification occurs on lysine (K) residues within a conserved N-terminal polyacidic serine (S) and K-rich (PASK) cluster. We show that polyphosphorylation negatively regulates Nsr1/Top1 interaction and impairs Top1 enzymatic activity. Physiological modulation of cellular levels of polyP regulates Top1 activity by modifying its polyphosphorylation status. We propose that polyphosphorylation adds an additional layer of regulation to nuclear signaling, where many PASK-containing proteins are known to play important roles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • DNA Topoisomerases, Type I / genetics
  • DNA Topoisomerases, Type I / metabolism*
  • Humans
  • Lysine / genetics
  • Lysine / metabolism*
  • Molecular Sequence Data
  • Nuclear Localization Signals / genetics
  • Nuclear Localization Signals / metabolism*
  • Polyphosphates / metabolism*
  • Protein Processing, Post-Translational*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Signal Transduction


  • Nuclear Localization Signals
  • Polyphosphates
  • Saccharomyces cerevisiae Proteins
  • DNA Topoisomerases, Type I
  • TOP1 protein, human
  • Lysine