Structural basis of co-translational N-myristoylation in humans

Denk, Timo; Monassa, Paul; Musial, Joanna; Berninghausen, Otto; Beatrix, Birgitta; Giglione, Carmela; Meinnel, Thierry; Beckmann, Roland (2026): Structural basis of co-translational N-myristoylation in humans. Nature Communications, 17: 1191. ISSN 2041-1723

Abstract

Modifications of proteins occurring during translation are critical for protein localization, stability and function. N-myristoylation is an essential N-terminal lipid modification catalyzed co-translationally by N-myristoyltransferases (NMTs) which have been identified as promising drug targets. However, its molecular basis in the context of the translating ribosome is not known. Here, we reveal the structural basis for co-translational N-myristoylation by NMT1 on the human ribosome by cryo-electron microscopy (cryo-EM). We show that NMT1 binds near the peptide tunnel exit and interacts with the nascent polypeptide-associated complex (NAC). Unlike other multi-enzyme complexes that act simultaneously, we find that methionine excision by methionine aminopeptidases and N-myristoylation occur sequentially via consecutive binding to the ribosome. Furthermore, our data suggest that NMT1 remains associated with elongating nascent chains, indicating a co-translational chaperone-like function in partnership with NAC. These insights provide a molecular foundation for the understanding of the co-translational N-myristoylation mechanism in humans.

• Doc-Type: Article (LMU)
• Organisational unit (Faculties): 18 Chemistry and Pharmacy > Department of Biochemistry
• DFG subject classification of scientific disciplines: Natural sciences
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 512515806
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 515291669
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 491502892