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Cited by 24RNA and protein synthesis mechanismsRNA modifications and cancerProtein Structure and Dynamics

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Multi-protein assemblies orchestrate co-translational enzymatic processing on the human ribosome

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Klein, Marius, Wild, Klemens, Sinning, Irmgard·2024·Nature Communications
DOI 10.1038/s41467-024-51964-9PMC PMC11372111

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Abstract

Nascent chains undergo co-translational enzymatic processing as soon as their N-terminus becomes accessible at the ribosomal polypeptide tunnel exit (PTE). In eukaryotes, N-terminal methionine excision (NME) by Methionine Aminopeptidases (MAP1 and MAP2), and N-terminal acetylation (NTA) by N-Acetyl-Transferase A (NatA), is the most common combination of subsequent modifications carried out on the 80S ribosome. How these enzymatic processes are coordinated in the context of a rapidly translating ribosome has remained elusive. Here, we report two cryo-EM structures of multi-enzyme complexes assembled on vacant human 80S ribosomes, indicating two routes for NME-NTA. Both assemblies form on the 80S independent of nascent chain substrates. Irrespective of the route, NatA occupies a non-intrusive ‘distal’ binding site on the ribosome which does not interfere with MAP1 or MAP2 binding nor with most other ribosome-associated factors (RAFs). NatA can partake in a coordinated, dynamic assembly with MAP1 through the hydra-like chaperoning function of the abundant Nascent Polypeptide-Associated Complex (NAC). In contrast to MAP1, MAP2 completely covers the PTE and is thus incompatible with NAC and MAP1 recruitment. Together, our data provide the structural framework for the coordinated orchestration of NME and NTA in protein biogenesis.

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Metadata

Authors
Klein, M., Wild, K., & Sinning, I.
Affiliations
Heidelberg University (DE)
Corresponding author
Sinning, Irmgard
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-09-03
Volume
15
Issue
1
Pages
7681-7681
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-51964-9
PMC
PMC11372111
OpenAlex
W4402189424
Cited by
24
References
2
Citations by year
2026: 8 · 2025: 14 · 2024: 2
FWCI
3.25
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Deutsche Forschungsgemeinschaft (SI 586-6)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
N-terminal methionine excision, N-terminal acetylation, methionine aminopeptidase 2, NATA, 80S ribosome, multienzyme complex, nascent polypeptide-associated complex, ribosome-associated factors, protein biogenesis, cryo-EM structure
MeSH terms
Acetylation, Binding Sites, Humans, Methionine, Models, Molecular, Protein Binding, Protein Processing, Post-Translational, Ribosomes, Protein Biosynthesis, Cryoelectron Microscopy

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