title: Global profiling of co- and post-translationally N-myristoylated proteomes in human cells.
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.
authors.affiliation: 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.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Thinon
authors.affiliation: Department of Chemistry, Imperial College London, Exhibition Road, London SW7 2AZ, UK.
authors.forename: Remigiusz A
authors.initials: RA
authors.lastname: Serwa
authors.affiliation: Department of Chemistry, Imperial College London, Exhibition Road, London SW7 2AZ, UK.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Broncel
authors.affiliation: York Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Brannigan
authors.affiliation: 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.
authors.forename: Ute
authors.initials: U
authors.lastname: Brassat
authors.affiliation: 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.
authors.forename: Megan H
authors.initials: MH
authors.lastname: Wright
authors.affiliation: Department of Chemistry, Imperial College London, Exhibition Road, London SW7 2AZ, UK.
authors.forename: William P
authors.initials: WP
authors.lastname: Heal
authors.affiliation: York Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD, UK.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Wilkinson
authors.affiliation: 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.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mann
authors.affiliation: 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.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Tate
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D006367:HeLa Cells; D006801:Humans; D019814:Myristic Acid / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D020543:Proteome / Q000235:genetics / Q000378:metabolism*
chemical_list: D020543:Proteome; D019814:Myristic Acid; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase