Global profiling of co- and post-translationally N-myristoylated proteomes in human cells

  • Nat Commun. 2014 Sep 26;5:4919. doi: 10.1038/ncomms5919.
Emmanuelle Thinon  1 ,  Remigiusz A Serwa  2 ,  Malgorzata Broncel  2 ,  James A Brannigan  3 ,  Ute Brassat  1 ,  Megan H Wright  4 ,  William P Heal  2 ,  Anthony J Wilkinson  3 ,  David J Mann  5 ,  Edward W Tate  4
Affiliations
  • 1. 1] Department of Chemistry, Imperial College London, Exhibition Road, London SW7 2AZ, UK [2] Department of Life Sciences, Imperial College London, Exhibition Road, London SW7 2AZ, UK.
  • 2. Department of Chemistry, Imperial College London, Exhibition Road, London SW7 2AZ, UK.
  • 3. York Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD, UK.
  • 4. 1] Department of Chemistry, Imperial College London, Exhibition Road, London SW7 2AZ, UK [2] Department of Chemistry, Institute of Chemical Biology, Imperial College London, Exhibition Road, London SW7 2AZ, UK.
  • 5. 1] Department of Life Sciences, Imperial College London, Exhibition Road, London SW7 2AZ, UK [2] Department of Chemistry, Institute of Chemical Biology, Imperial College London, Exhibition Road, London SW7 2AZ, UK.
PMID: 25255805 DOI: 10.1038/ncomms5919
Abstract

Protein N-myristoylation is a ubiquitous co- and post-translational modification that has been implicated in the development and progression of a range of human diseases. Here, we report the global N-myristoylated proteome in human cells determined using quantitative chemical proteomics combined with potent and specific human N-myristoyltransferase (NMT) inhibition. Global quantification of N-myristoylation during normal growth or Apoptosis allowed the identification of >100 N-myristoylated proteins, >95% of which are identified for the first time at endogenous levels. Furthermore, quantitative dose response for inhibition of N-myristoylation is determined for >70 substrates simultaneously across the proteome. Small-molecule inhibition through a conserved substrate-binding pocket is also demonstrated by solving the crystal structures of inhibitor-bound NMT1 and NMT2. The presented data substantially expand the known repertoire of co- and post-translational N-myristoylation in addition to validating tools for the pharmacological inhibition of NMT in living cells.