The structural basis for RNA slicing by human Argonaute2
Open accessPublished version of a preprint
Abstract
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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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
UniProt: the Universal Protein Knowledgebase in 2023
The UniProt Consortium, Bateman, A., Martin, M.-J., Orchard, S., Magrane, M., Ahmad, S., Alpi, E., Bowler-Barnett, E. H., Britto, R., Bye-A-Jee, H., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkac1052 · Cited by 7,210 · see citing works
High-Throughput Analysis Reveals Rules for Target RNA Binding and Cleavage by AGO2
Becker, W. R., Ober-Reynolds, B., Jouravleva, K., Jolly, S. M., Zamore, P. D., & Greenleaf, W. J. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.06.012 · Cited by 161 · see citing works
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- 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.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2025-01
- Volume
- 44
- Issue
- 1
- Pages
- 115166
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC11893014
- OpenAlex
- W4405926305
- Cited by
- 32
- References
- 3
- Citations by year
- 2026: 19 · 2025: 12 · 2024: 1
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- 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
- Howard Hughes Medical Institute
- National Institutes of Health (GM118135)
- Richard and Susan Smith Family Foundation
- National Science Foundation Graduate Research Fellowship Program
- Alex's Lemonade Stand Foundation for Childhood Cancer
- Office of Graduate Education, Massachusetts Institute of Technology
- National Science Foundation
- 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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