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Cell Rep. 2013 Jun 27;3(6):1901-9. doi: 10.1016/j.celrep.2013.05.033. Epub 2013 Jun 6.

The making of a slicer: activation of human Argonaute-1.

Author information

  • 1W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.

Abstract

Argonautes are the central protein component in small RNA silencing pathways. Of the four human Argonautes (hAgo1-hAgo4) only hAgo2 is an active slicer. We determined the structure of hAgo1 bound to endogenous copurified RNAs to 1.75 Å resolution and hAgo1 loaded with let-7 microRNA to 2.1 Å. Both structures are strikingly similar to the structures of hAgo2. A conserved catalytic tetrad within the PIWI domain of hAgo2 is required for its slicing activity. Completion of the tetrad, combined with a mutation on a loop adjacent to the active site of hAgo1, results in slicer activity that is substantially enhanced by swapping in the N domain of hAgo2. hAgo3, with an intact tetrad, becomes an active slicer by swapping the N domain of hAgo2 without additional mutations. Intriguingly, the elements that make Argonaute an active slicer involve a sophisticated interplay between the active site and more distant regions of the enzyme.

Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

PMID:
23746446
[PubMed - indexed for MEDLINE]
PMCID:
PMC3769929
Free PMC Article

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