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

TY - JOUR

T1 - Global profiling of co- and post-translationally N-myristoylated proteomes in human cells

AU - Thinon, Emmanuelle

AU - Serwa, Remigiusz A.

AU - Broncel, Malgorzata

AU - Brannigan, James A.

AU - Brassat, Ute

AU - Wright, Megan H.

AU - Heal, William P.

AU - Wilkinson, Anthony J.

AU - Mann, David J.

AU - Tate, Edward W.

PY - 2014/9/26

Y1 - 2014/9/26

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84909634606&partnerID=8YFLogxK

U2 - 10.1038/ncomms5919

DO - 10.1038/ncomms5919

M3 - Article

AN - SCOPUS:84909634606

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 4919

ER -