The Ban lab in collaboration with the Deuerling and Shan labs could elucidate in human cells the mechanism of co-translational N-myristoylation. This modification affects the function and localization of the modified proteins and the responsible proteins, N-myristoyltransferases (NMTs), are considered drug targets to combat viral infections and cancer. Nascent polypeptide-associated complex (NAC) recruits NMTs after the N-terminal methionine has been excised, which makes the myristoylation site accessible.
Highlights
- NAC recruits N-myristoyltransferases (NMTs) to translating ribosomes
- N-terminal methionine excision unmasks NMT motifs in nascent chains
- Structure-function analysis reveals molecular interplay of NMTs, METAP1 and NatA
Summary
N-myristoyltransferases (NMTs) cotranslationally transfer the fatty acid myristic acid to the N terminus of newly synthesized proteins, regulating their function and cellular localization. These enzymes are important drug targets for the treatment of cancer and viral infections. N-myristoylation of nascent proteins occurs specifically on N-terminal glycine residues after the excision of the initiator methionine by methionine aminopeptidases (METAPs). How NMTs interact with ribosomes and gain timely and specific access to their substrates remains unknown. Here, we show that human NMT1 exchanges with METAP1 at the ribosomal tunnel exit to form an active cotranslational complex together with the nascent polypeptide-associated complex (NAC). NMT1 binding is sequence selective and specifically triggered by methionine excision, which exposes the N-myristoylation motif in the nascent chain. The revealed mode of interaction of NMT1 with NAC and the methionine-cleaved nascent protein elucidates how a specific subset of proteins can be efficiently N-myristoylated in human cells.
Read the Publication in Molecular Cell
Figure, highlights, summary and title from Gamerdinger, Echeverria (2025) Mol Cell published under a CC BY 4.0 license.