Dataset Information

Antagonistic roles for Ataxin-2 structured and disordered domains in RNP condensation.

ABSTRACT: Ataxin-2 (Atx2) is a translational control molecule mutated in spinocerebellar ataxia type II and amyotrophic lateral sclerosis. While intrinsically disordered domains (IDRs) of Atx2 facilitate mRNP condensation into granules, how IDRs work with structured domains to enable positive and negative regulation of target mRNAs remains unclear. Using the Targets of RNA-Binding Proteins Identified by Editing technology, we identified an extensive data set of Atx2-target mRNAs in the Drosophila brain and S2 cells. Atx2 interactions with AU-rich elements in 3'UTRs appear to modulate stability/turnover of a large fraction of these target mRNAs. Further genomic and cell biological analyses of Atx2 domain deletions demonstrate that Atx2 (1) interacts closely with target mRNAs within mRNP granules, (2) contains distinct protein domains that drive or oppose RNP-granule assembly, and (3) has additional essential roles outside of mRNP granules. These findings increase the understanding of neuronal translational control mechanisms and inform strategies for Atx2-based interventions under development for neurodegenerative disease.

SUBMITTER: Singh A

PROVIDER: S-EPMC7946432 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Antagonistic roles for Ataxin-2 structured and disordered domains in RNP condensation.

Singh Amanjot A Hulsmeier Joern J Kandi Arvind Reddy AR Pothapragada Sai Shruti SS Hillebrand Jens J Petrauskas Arnas A Agrawal Khushboo K Rt Krishnan K Thiagarajan Devasena D Jayaprakashappa Deepa D VijayRaghavan K K Ramaswami Mani M Bakthavachalu Baskar B

eLife 20210310

Ataxin-2 (Atx2) is a translational control molecule mutated in spinocerebellar ataxia type II and amyotrophic lateral sclerosis. While intrinsically disordered domains (IDRs) of Atx2 facilitate mRNP condensation into granules, how IDRs work with structured domains to enable positive and negative regulation of target mRNAs remains unclear. Using the Targets of RNA-Binding Proteins Identified by Editing technology, we identified an extensive data set of Atx2-target mRNAs in the <i>Drosophila</i> b ...[more]

PMID: 33689682

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Project description:UNLABELLED:The anti-? factor NepR plays a central role in regulation of the general stress response (GSR) in alphaproteobacteria. This small protein has two known interaction partners: its cognate extracytoplasmic function (ECF) ? factor and the anti-anti-? factor, PhyR. Stress-dependent phosphorylation of PhyR initiates a protein partner switch that promotes phospho-PhyR binding to NepR, which frees ECF ? to activate transcription of genes required for cell survival under adverse or fluctuating conditions. We have defined key functional roles for structured and intrinsically disordered domains of Caulobacter crescentus NepR in partner binding and activation of GSR transcription. We further demonstrate that NepR strongly stimulates the rate of PhyR phosphorylation in vitro and that this effect requires the structured and disordered domains of NepR. This result provides evidence for an additional layer of GSR regulation in which NepR directly influences activation of its binding partner, PhyR, as an anti-anti-? factor. We conclude that structured and intrinsically disordered domains of NepR coordinately control multiple functions in the GSR signaling pathway, including core protein partner switch interactions and pathway activation by phosphorylation. IMPORTANCE:Anti-? factors are key molecular participants in a range of adaptive responses in bacteria. The anti-? factor NepR plays a vital role in a multiprotein partner switch that governs general stress response (GSR) transcription in alphaproteobacteria. We have defined conserved and unconserved features of NepR structure that determine its function as an anti-? factor and uncovered a functional role for intrinsically disordered regions of NepR in partner binding events required for GSR activation. We further demonstrate a novel function for NepR as an enhancer of PhyR phosphorylation; this activity also requires the disordered domains of NepR. Our results provide evidence for a new layer of GSR regulatory control in which NepR directly modulates PhyR phosphorylation and, hence, activation of the GSR.

Dataset Information

Antagonistic roles for Ataxin-2 structured and disordered domains in RNP condensation.

Publications

Antagonistic roles for Ataxin-2 structured and disordered domains in RNP condensation.

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