A shape-shifting nuclease unravels structured RNA

Meze, Katarina, Axhemi, Armend, Thomas, Dennis, Doymaz, Ahmet, Joshua-Tor, Leemor (2021) A shape-shifting nuclease unravels structured RNA. bioRxiv. (Submitted)

DOI: 10.1101/2021.11.30.470623


RNA turnover pathways ensure appropriate gene expression levels by eliminating unwanted transcripts that may otherwise interfere with cellular programs. The enzyme Dis3-like protein 2 (Dis3L2) is a 3’-5’ exoribonuclease that, through its RNA turnover activity, plays a critical role in human development1. Dis3L2 can independently degrade structured substrates and its targets include many coding and non-coding 3’-uridylated RNAs1–5. While the basis for Dis3L2’s substrate recognition has been well-characterized6, the mechanism of structured RNA degradation by this family of enzymes is unknown. We characterized the discrete steps of the degradation cycle by determining electron cryo-microscopy structures representing snapshots along the RNA turnover pathway and measuring kinetic parameters for single-stranded (ss) and double-stranded (ds) RNA processing. We discovered a dramatic conformational change that is triggered by the dsRNA, involving repositioning of two cold shock domains by 70 Å. This movement exposes a trihelix-linker region, which acts as a wedge to separate the two RNA strands. Furthermore, we show that the trihelix linker is critical for dsRNA, but not ssRNA, degradation. These findings reveal the conformational plasticity of this enzyme, and detail a novel mechanism of structured RNA degradation.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA expression
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
CSHL Authors:
Communities: CSHL labs > Furukawa lab
CSHL labs > Joshua-Tor lab
School of Biological Sciences > Publications
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 2021
Date Deposited: 03 Oct 2023 20:18
Last Modified: 29 Feb 2024 19:37
Related URLs:
URI: https://repository.cshl.edu/id/eprint/41116

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