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Target binding triggers hierarchical phosphorylation of human Argonaute-2 to promote target release

View ORCID ProfileBrianna Bibel, View ORCID ProfileElad Elkayam, Steve Silletti, Elizabeth A Komives, View ORCID ProfileLeemor Joshua-Tor
doi: https://doi.org/10.1101/2022.01.06.475261
Brianna Bibel
1Cold Spring Harbor Laboratory School of Biological Sciences, Cold Spring Harbor, NY, 11724, USA
2Howard Hughes Medical Institute, W. M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA
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Elad Elkayam
2Howard Hughes Medical Institute, W. M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA
3Ventus Therapeutics, Waltham, Massachusetts 02453
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Steve Silletti
4Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA
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Elizabeth A Komives
4Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA
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Leemor Joshua-Tor
1Cold Spring Harbor Laboratory School of Biological Sciences, Cold Spring Harbor, NY, 11724, USA
2Howard Hughes Medical Institute, W. M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA
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  • For correspondence: leemor@cshl.edu
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Abstract

Argonaute (Ago) proteins play a central role in post-transcriptional gene regulation through RNA interference (RNAi). Agos bind small RNAs (sRNAs) including small interfering RNAs (siRNAs) and microRNAs (miRNAs) to form the functional core of the RNA Induced Silencing Complex (RISC). The sRNA is used as a guide to target mRNAs containing either partially or fully complementary sequences, ultimately leading to down regulation of the corresponding proteins. It was previously shown that the kinase CK1α phosphorylates a cluster of residues in the eukaryotic insertion (EI) of Ago, leading to the alleviation of miRNA-mediated repression through an undetermined mechanism. We show that binding of miRNA-loaded human Ago2 to target RNA with complementarity to the seed and 3’ supplemental regions of the miRNA primes the EI for hierarchical phosphorylation by CK1α. The added negative charges electrostatically promote target release, freeing Ago to seek out additional targets once it is dephosphorylated. The high conservation of potential phosphosites in the EI suggests that such a regulatory strategy may be a shared mechanism for regulating miRNA-mediated repression.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 06, 2022.
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Target binding triggers hierarchical phosphorylation of human Argonaute-2 to promote target release
Brianna Bibel, Elad Elkayam, Steve Silletti, Elizabeth A Komives, Leemor Joshua-Tor
bioRxiv 2022.01.06.475261; doi: https://doi.org/10.1101/2022.01.06.475261
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Target binding triggers hierarchical phosphorylation of human Argonaute-2 to promote target release
Brianna Bibel, Elad Elkayam, Steve Silletti, Elizabeth A Komives, Leemor Joshua-Tor
bioRxiv 2022.01.06.475261; doi: https://doi.org/10.1101/2022.01.06.475261

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