A brave new world of RNA-binding proteins

Hentze, Matthias W.; Castelló, Alfredo; Schwarzl, Thomas; Preiß, Thomas

doi:10.1038/nrm.2017.130

Cited by 1,288 publications

(1,303 citation statements)

References 165 publications

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“…It has been recently reported that PP2A-B56 recognises and binds a LxxIxE SLiM on target substrates [25][26][27]. Pull-down assays showed only wild-type (WT) Apc1-loop 500 significantly bound 35 S-labelled in vitro-translated B56c in anaphase extracts (lane 14), compared with MBP-alone or MBP-fused Apc1-loop 500-Δ11 (lanes 13 and 15). Primary sequence inspection of those domains has identified one such SLiM (LSPVPE) in a predicted loop domain of Apc1 (515-584 in Xenopus Apc1, hereinafter referred to as Apc1-loop 500 ) that is located in the N-terminal WD40 domain of Apc1.…”

Section: Resultsmentioning

confidence: 96%

“…Intriguingly, a number of recently identified RNA binding proteins bind to RNAs via disordered loop regions [35]. The Apc3-loop mediates efficient phosphorylation of Apc3 and Apc1 by directly recruiting Cks-Cdk1-cyclin B, whereas the Apc1-loop 300 acts as a phosphorylation-mediated conformational switch, permitting association with Cdc20.…”

Section: Pp2a-b56 Mediates Dephosphorylation Of Cdc20mentioning

confidence: 99%

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PP2A‐B56 binds to Apc1 and promotes Cdc20 association with the APC/C ubiquitin ligase in mitosis

Fujimitsu

Yamano

2019

EMBO Reports

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Cell cycle progression and genome stability are regulated by a ubiquitin ligase, the anaphase-promoting complex/cyclosome (APC/C). Cyclin-dependent kinase 1 (Cdk1) has long been implicated in APC/ C activation; however, the molecular mechanisms of governing this process in vivo are largely unknown. Recently, a Cdk1-dependent phosphorylation relay within Apc3-Apc1 subunits has been shown to alleviate Apc1-mediated auto-inhibition by which a mitotic APC/ C co-activator Cdc20 binds to and activates the APC/C. However, the underlying mechanism for dephosphorylation of Cdc20 and APC/C remains elusive. Here, we show that a disordered loop domain of Apc1 (Apc1-loop 500 ) directly binds the B56 regulatory subunit of protein phosphatase 2A (PP2A) and stimulates Cdc20 loading to the APC/C. Using the APC/C reconstitution system in Xenopus egg extracts, we demonstrate that mutations in Apc1loop 500 that abolish B56 binding decrease Cdc20 loading and APC/ C-dependent ubiquitylation. Conversely, a non-phosphorylatable mutant Cdc20 can efficiently bind the APC/C even when PP2A-B56 binding is impeded. Furthermore, PP2A-B56 preferentially dephosphorylates Cdc20 over the Apc1 inhibitory domain. These results indicate that Apc1-loop 500 plays a role in dephosphorylating Cdc20, promoting APC/C-Cdc20 complex formation in mitosis.

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Section: Resultsmentioning

confidence: 96%

Section: Pp2a-b56 Mediates Dephosphorylation Of Cdc20mentioning

confidence: 99%

PP2A‐B56 binds to Apc1 and promotes Cdc20 association with the APC/C ubiquitin ligase in mitosis

Fujimitsu

Yamano

2019

EMBO Reports

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“…In addition, with the identification of hundreds of new RBPs, many of which lack conventional RBDs (reviewed in [446]), upcoming research should aim at analyzing their RNA targets, protein partners and specific housekeeping roles, hoping to complement existing knowledge on the regulation of gene expression in neurons.…”

Section: Resultsmentioning

confidence: 99%

Unraveling the Pathways to Neuronal Homeostasis and Disease: Mechanistic Insights into the Role of RNA-Binding Proteins and Associated Factors

Ravanidis

Kattan

Doxakis

2018

IJMS

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The timing, dosage and location of gene expression are fundamental determinants of brain architectural complexity. In neurons, this is, primarily, achieved by specific sets of trans-acting RNA-binding proteins (RBPs) and their associated factors that bind to specific cis elements throughout the RNA sequence to regulate splicing, polyadenylation, stability, transport and localized translation at both axons and dendrites. Not surprisingly, misregulation of RBP expression or disruption of its function due to mutations or sequestration into nuclear or cytoplasmic inclusions have been linked to the pathogenesis of several neuropsychiatric and neurodegenerative disorders such as fragile-X syndrome, autism spectrum disorders, spinal muscular atrophy, amyotrophic lateral sclerosis and frontotemporal dementia. This review discusses the roles of Pumilio, Staufen, IGF2BP, FMRP, Sam68, CPEB, NOVA, ELAVL, SMN, TDP43, FUS, TAF15, and TIA1/TIAR in RNA metabolism by analyzing their specific molecular and cellular function, the neurological symptoms associated with their perturbation, and their axodendritic transport/localization along with their target mRNAs as part of larger macromolecular complexes termed ribonucleoprotein (RNP) granules.

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“…The vast protein complement of mRNPs has been illuminated (Hentze et al., 2018) and is presumed to change as mRNPs progress through their life. However, the understanding of mechanisms and consequences of mRNP composition change remains confined to only a handful of its components.…”

Section: Introductionmentioning

confidence: 99%

The Exon Junction Complex Undergoes a Compositional Switch that Alters mRNP Structure and Nonsense-Mediated mRNA Decay Activity

et al. 2018

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SUMMARY The exon junction complex (EJC) deposited upstream of mRNA exon junctions shapes structure, composition, and fate of spliced mRNA ribonucleoprotein particles (mRNPs). To achieve this, the EJC core nucleates assembly of a dynamic shell of peripheral proteins that function in diverse post-transcriptional processes. To illuminate consequences of EJC composition change, we purified EJCs from human cells via peripheral proteins RNPS1 and CASC3. We show that the EJC originates as an SR-rich mega-dalton-sized RNP that contains RNPS1 but lacks CASC3. Sometime before or during translation, the EJC undergoes compositional and structural remodeling into an SR-devoid monomeric complex that contains CASC3. Surprisingly, RNPS1 is important for nonsense-mediated mRNA decay (NMD) in general, whereas CASC3 is needed for NMD of only select mRNAs. The switch to CASC3-EJC slows down NMD. Overall, the EJC compositional switch dramatically alters mRNP structure and specifies two distinct phases of EJC-dependent NMD.

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A brave new world of RNA-binding proteins

Cited by 1,288 publications

References 165 publications

PP2A‐B56 binds to Apc1 and promotes Cdc20 association with the APC/C ubiquitin ligase in mitosis

PP2A‐B56 binds to Apc1 and promotes Cdc20 association with the APC/C ubiquitin ligase in mitosis

Unraveling the Pathways to Neuronal Homeostasis and Disease: Mechanistic Insights into the Role of RNA-Binding Proteins and Associated Factors

The Exon Junction Complex Undergoes a Compositional Switch that Alters mRNP Structure and Nonsense-Mediated mRNA Decay Activity

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