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PreprintCited 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 10.1101/2024.06.14.599006PMC PMC11372111

Preprint — published as 10.1038/s41467-024-51964-9 · Paper page

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Abstract

Most nascent chains undergo rapid 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 set of subsequent modifications carried out on the ribosome. How these two enzymatic processes are coordinated in quick succession in the context of a rapidly translating ribosome has remained elusive. Here, we report that human NatA occupies a non-intrusive ‘distal’ binding site on the ribosome which does not interfere with most other ribosome associated factors (RAFs). In this position, NatA can partake in a coordinated and dynamic assembly with MAP1 through a complex scaffolding function of the abundant Nascent Polypeptide Associated Complex (NAC). Alternatively, MAP2 can co-occupy the PTE with NatA in preparation for successive NME and NTA. In contrast to MAP1, MAP2 completely covers the PTE and is thus incompatible with NAC and MAP1 recruitment. Both assemblies can compile on the human ribosome independent of nascent chain substrates. Together, our structures provide the structural framework for the rapid 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
openRxiv
Published
2024-06-14
Volume
15
Issue
1
Pages
7681-7681
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2024.06.14.599006
PMC
PMC11372111
OpenAlex
W4402189424
Cited by
24
References
1
Citations by year
2026: 8 · 2025: 14 · 2024: 2
FWCI
3.27
Type
journal article
Language
en
Open access
Licence
cc-by
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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