Proteome-wide probing of the dual NMT-dependent myristoylation tradeoff unveils potent, mechanism-based suicide inhibitors - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Pré-Publication, Document De Travail Année : 2021

Proteome-wide probing of the dual NMT-dependent myristoylation tradeoff unveils potent, mechanism-based suicide inhibitors

Résumé

ABSTRACT N-myristoyltransferases (NMTs) catalyze protein myristoylation, a major and ubiquitous lipid modification. Originally thought to modify only N-terminal glycine α-amino groups (G-myristoylation), NMTs are now known to modify lysine ε-amino groups (K-myristoylation), the significance of which is uncertain. Here we exploited systematic structural proteomics analyses and a novel pipeline involving the Shigella IpaJ protease to discriminate K- and G-myristoylation with unprecedented accuracy and identify the specific features driving each modification. NMT-dependent K-myristoylation occurs post-translationally and only on lysines 1, 2, or 3 following G-myristoylation or caspase cleavage. Direct interactions between the substrate’s reactive amino group and the NMT catalytic base slow K-myristoylation catalysis. IpaJ unmasked novel K-myristoylation sites in a dozen human proteins. The unique properties of NMT-driven K-myristoylation allowed us to design potent, mechanism-based suicide NMT inhibitors. These analyses unravel the respective paths towards K-myristoylation, G-myristoylation, or NMT inhibition, which rely on a very subtle tradeoff embracing the chemical landscape around the reactive group. SIGNIFICANCE STATEMENT We report the specific and unique elements guiding N-myristoyltransferase to either alpha or epsilon myristoylation, allowing us to establish the post-translational nature of N-myristoyltransferase-dependent lysine myristoylation and design novel, potent N-myristoyltransferase inhibitors.

Dates et versions

hal-03398842 , version 1 (23-10-2021)

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Citer

Frédéric Rivière, Cyril Dian, Rémi Dutheil, Carmela Giglione, Thierry Meinnel. Proteome-wide probing of the dual NMT-dependent myristoylation tradeoff unveils potent, mechanism-based suicide inhibitors. 2021. ⟨hal-03398842⟩
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