A shape-shifting nuclease unravels structured RNA

Meze, Katarina, Axhemi, Armend, Thomas, Dennis R, Doymaz, Ahmet, Joshua-Tor, Leemor (February 2023) A shape-shifting nuclease unravels structured RNA. Nature Structural and Molecular Biology. ISSN 1545-9993 (Public Dataset)

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Abstract

RNA turnover pathways ensure appropriate gene expression levels by eliminating unwanted transcripts. Dis3-like 2 (Dis3L2) is a 3'-5' exoribonuclease that plays a critical role in human development. Dis3L2 independently degrades structured substrates, including coding and noncoding 3' uridylated RNAs. While the basis for Dis3L2's substrate recognition has been well characterized, the mechanism of structured RNA degradation by this family of enzymes is unknown. We characterized the discrete steps of the degradation cycle by determining cryogenic electron microscopy structures representing snapshots along the RNA turnover pathway and measuring kinetic parameters for RNA processing. We discovered a dramatic conformational change that is triggered by double-stranded RNA (dsRNA), repositioning 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 single-stranded RNA, degradation. These findings reveal the conformational plasticity of Dis3L2 and detail a mechanism of structured RNA degradation.

Item Type:	Paper
Subjects:	Investigative techniques and equipment bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA expression Investigative techniques and equipment > microscopy > electron microscopy Investigative techniques and equipment > microscopy bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > ribonuclease
CSHL Authors:	Meze, Katarina Axhemi, Armend Thomas, Dennis R Joshua-Tor, Leemor
Communities:	CSHL Cancer Center Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL Cancer Center Shared Resources > Mass Spectrometry Service CSHL labs > Furukawa lab CSHL labs > Joshua-Tor lab School of Biological Sciences > Publications
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	23 February 2023
Date Deposited:	28 Feb 2023 18:36
Last Modified:	29 Feb 2024 19:37
PMCID:	PMC10023572
Dataset ID:	PDB: 8E28 PDB: 8E27 EMDB: 27827 EMDB: 27828 PDB: 8E29 EMDB: 27829 PDB: 8E2A EMDB: 27830 EMDB: 27831
URI:	https://repository.cshl.edu/id/eprint/40846

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