title: Protein polyphosphorylation of lysine residues by inorganic polyphosphate.
abstract: 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.
authors.affiliation: Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK. Electronic address: c.azevedo@ucl.ac.uk.
authors.forename: Cristina
authors.initials: C
authors.lastname: Azevedo
authors.affiliation: Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Livermore
authors.affiliation: Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK. Electronic address: dmcbado@ucl.ac.uk.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Saiardi
mesh_terms: D020816:Amino Acid Motifs; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism*; D011122:Polyphosphates / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019913:Nuclear Localization Signals; D011122:Polyphosphates; D029701:Saccharomyces cerevisiae Proteins; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D008239:Lysine