9ndp
Structure of stalled ribosome and nascent chain in complex with NMT2 and NAC
Structural highlights
FunctionRS27A_RABIT Exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in proteotoxic stress response and cell cycle; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.[UniProtKB:P62979] Component of the 40S subunit of the ribosome (PubMed:23873042, PubMed:25601755, PubMed:27863242, PubMed:30517857). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit (PubMed:23873042, PubMed:25601755, PubMed:27863242, PubMed:30517857). During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:23873042, PubMed:25601755, PubMed:27863242, PubMed:30517857).[1] [2] [3] [4] Publication Abstract from PubMedN-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. NAC couples protein synthesis with nascent polypeptide myristoylation on the ribosome.,Zdancewicz S, Maldosevic E, Malezyna K, Jomaa A EMBO J. 2025 Aug 26. doi: 10.1038/s44318-025-00548-4. PMID:40859030[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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