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PreprintCited by 32RNA Interference and Gene DeliveryCRISPR and Genetic EngineeringRNA regulation and disease

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The structural basis for RNA slicing by human Argonaute2

Open access
Mohamed, Abdallah A., Wang, Peter Y., Bartel, David P., Vos, Seychelle M.·2024·Cell Reports
DOI 10.1101/2024.08.19.608718PMC PMC11893014

Preprint — published as 10.1016/j.celrep.2024.115166 · Paper page

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Abstract

SUMMARY: Argonaute (AGO) proteins associate with guide RNAs to form complexes that slice transcripts that pair to the guide. This slicing drives post-transcriptional gene-silencing pathways that are essential for many eukaryotes and the basis for new clinical therapies. Despite this importance, structural information on eukaryotic AGOs in a fully paired, slicing-competent conformation—hypothesized to be intrinsically unstable—has been lacking. Here we present the cryogenic-electron microscopy structure of a human AGO−guide complex bound to a fully paired target, revealing structural rearrangements that enable this conformation. Critically, the N domain of AGO rotates to allow the RNA full access to the central channel and forms contacts that license rapid slicing. Moreover, a conserved loop in the PIWI domain secures the RNA near the active site to enhance slicing rate and specificity. These results explain how AGO accommodates targets possessing the pairing specificity typically observed in biological and clinical slicing substrates.

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Metadata

Authors
Mohamed, A. A., Wang, P. Y., Bartel, D. P., & Vos, S. M.
Affiliations
  • Massachusetts Institute of Technology (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
  • Bartel, David P.
  • Vos, Seychelle M.
ORCID
Venue
Cell Reports
Publisher
openRxiv
Published
2024-08-20
Volume
44
Issue
1
Pages
115166-115166
ISSN
2211-1247 (ISSN-L)
DOI
10.1101/2024.08.19.608718
PMC
PMC11893014
OpenAlex
W4405926305
Cited by
32
References
1
Citations by year
2026: 19 · 2025: 12 · 2024: 1
FWCI
4.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by)
  • PubMed Central (acceptedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Science Foundation
  • Howard Hughes Medical Institute
  • Richard and Susan Smith Family Foundation
  • Alex's Lemonade Stand Foundation for Childhood Cancer
  • National Institutes of Health
  • Office of Graduate Education, Massachusetts Institute of Technology
  • National Institute of General Medical Sciences (DP2GM146254, R35GM118135)
  • National Science Foundation Graduate Research Fellowship Program
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords
Argonaute 2, RNA interference, post-transcriptional gene silencing, PIWI domain, active site, cryo-EM structure

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