N-glycine myristoylation allows for reversible association of newly synthesized proteins with membranes to regulate essential functions such as cellular signaling and stress responses. This process can be catalyzed during protein synthesis by N-myristoyltransferases (NMTs), and its dysregulation has been implicated both in cancer and heart disease. Although the nascent polypeptide-associated complex (NAC) orchestrates the binding of several co-translational processing factors on ribosomes, its role in facilitating nascent protein myristoylation by NMT2 remains unclear. Here, we show that NAC mediates binding of NMT2 to translating ribosomes, which together form an extended channel that guides the nascent chain as it emerges from the polypeptide exit tunnel to the catalytic site of NMT2. Furthermore, the ternary ribosome:NMT2:NAC complex is stabilized by a ribosomal RNA clamp that, together with NAC, orients NMT2 on the ribosomal surface for co-translational myristoylation of nascent chains. Our work uncovers the molecular mechanism coupling protein synthesis to nascent protein myristoylation and underscores the role of NAC as a master regulator of protein biogenesis on the ribosome.

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Journal Article

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Zdancewicz S, Maldosevic E, Malezyna K, Jomaa A

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