Structural and large-scale analysis unveil the intertwined paths promoting NMT-catalyzed lysine and glycine myristoylation - Archive ouverte HAL Access content directly
Journal Articles Journal of Molecular Biology Year : 2022

Structural and large-scale analysis unveil the intertwined paths promoting NMT-catalyzed lysine and glycine myristoylation

(1, 2) , (1, 2) , (1, 2) , (1, 2) , (1, 2) , (1, 2)
1
2

Abstract

N-myristoyltransferases (NMTs) catalyze protein myristoylation, a lipid modification crucial for cell survival and a range of pathophysiological processes. Originally thought to modify only N-terminal glycine α-amino groups (G-myristoylation), NMTs were recently shown to also modify lysine ε-amino groups (K-myristoylation). However, the clues ruling NMTdependent K-myristoylation and the full range of targets are currently unknown. Here we combine mass spectrometry, kinetic studies, in silico analysis, and crystallography to identify the specific features driving each modification. We show that direct interactions between the substrate's reactive amino group and the NMT catalytic base promote K-myristoylation but with poor efficiency compared to G-myristoylation, which instead uses a water-mediated interaction. We provide evidence of depletion of proteins with NMT-dependent Kmyristoylation motifs in humans, suggesting evolutionary pressure to prevent this modification in favor of G-myristoylation. In turn, we reveal that K-myristoylation may only result from post-translational events. Our studies finally unravel the respective paths towards Kmyristoylation or G-myristoylation, which rely on a very subtle tradeoff embracing the chemical landscape around the reactive group.
Fichier principal
Vignette du fichier
Riviere22092022final.pdf (1.78 Mo) Télécharger le fichier
Origin : Files produced by the author(s)

Dates and versions

hal-03793088 , version 1 (30-09-2022)

Identifiers

Cite

Frédéric Rivière, Cyril Dian, Rémi F. Dutheil, Paul Monassa, Carmela Giglione, et al.. Structural and large-scale analysis unveil the intertwined paths promoting NMT-catalyzed lysine and glycine myristoylation. Journal of Molecular Biology, 2022, 434 (22), pp.67843. ⟨10.1016/j.jmb.2022.167843⟩. ⟨hal-03793088⟩
40 View
13 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More