Paper Info
Title
A Mechanistic Model for the Hsp90-Driven Opening of Human Argonaute.
Abstract
The assembly of RNA-induced silencing complex (RISC) is a key process in small RNA-mediated gene silencing. Loading of small RNAs into Argonaute (Ago), the key player protein in the process, has been shown to depend on the Hsp90 chaperone machinery. Experimental single-molecule data indicate that ATP binding to the chaperone facilitates the conformational changes leading to the open state of Ago essential to form a complex with small-RNA duplexes. Yet, no atomic-level description of the dynamic mechanisms and protein-protein interactions underpinning Hsp90-mediated Ago conformational activation is available. Here we investigate the functionally oriented structural and dynamic features of Hsp90-human Ago (hAgo2) complexes in different ligand states by integrating protein-protein docking techniques, all-atom MD simulations, and novel methods of analysis of protein internal dynamics and energetics. On this basis, we develop a structural-dynamic model of the mechanisms underlying the chaperone-assisted human RISC assembly. Our approach unveils the large conformational variability displayed by hAgo2 in the unbound vs the Hsp90-bound states. In this context, several hAgo2 states are found to coexist in isolation, while Hsp90 selects and stabilizes the active form. Hsp90 binding modulates the conformational plasticity of hAgo2 (favoring its opening) by modifying the patterns of hAgo2 intramolecular interactions. Finally, we identify a series of experimentally verifiable key sites that can be mutated to modulate Hsp90-mediated hAgo2 conformational response and ability to bind RNA.
Year
DOI
Venue
2020
10.1021/acs.jcim.0c00053
JOURNAL OF CHEMICAL INFORMATION AND MODELING
DocType
Volume
Issue
Journal
60
3
ISSN
Citations 
PageRank 
1549-9596
0
0.34
References 
Authors
0
3
Name
Order
Citations
PageRank
Silvia Rinaldi100.34
Giorgio Colombo24911.77
Antonella Paladino300.34