Polyanions provide selective control of APC/C interactions with the activator subunit

Mizrak, Arda; Morgan, David

doi:10.1038/s41467-019-13864-1

Cited by 11 publications

(12 citation statements)

References 61 publications

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“…Through RNA mimicry, viral RNAs can mimic the shape of cellular tRNAs ( Colussi et al, 2014 ). RNA can also mimic the shape of proteins and protein interaction surfaces ( Athanassiou et al, 2004 ; Shao and Hegde, 2016 ; Mizrak and Morgan, 2019 ). Here, we found that the network structure and morphogenesis of the tubular ER that is generated by proteins and lipids can be mimicked by phase-separated condensates formed by protein and RNA.…”

Section: Discussionmentioning

confidence: 99%

In vivo reconstitution finds multivalent RNA–RNA interactions as drivers of mesh-like condensates

Zheng

Xie

et al. 2021

eLife

103

104

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Liquid-like condensates have been thought to be sphere-like. Recently, various condensates with filamentous morphology have been observed in cells. One such condensate is the TIS granule network that shares a large surface area with the rough endoplasmic reticulum and is important for membrane protein trafficking. It has been unclear how condensates with mesh-like shapes, but dynamic protein components are formed. In vitro and in vivo reconstitution experiments revealed that the minimal components are a multivalent RNA-binding protein that concentrates RNAs that are able to form extensive intermolecular mRNA-mRNA interactions. mRNAs with large unstructured regions have a high propensity to form a pervasive intermolecular interaction network that acts as condensate skeleton. The underlying RNA matrix prevents full fusion of spherical liquid-like condensates, thus driving the formation of irregularly shaped membraneless organelles. The resulting large surface area may promote interactions at the condensate surface and at the interface with other organelles.

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Section: Discussionmentioning

confidence: 99%

In vivo reconstitution finds multivalent RNA–RNA interactions as drivers of mesh-like condensates

Zheng

Xie

et al. 2021

eLife

103

104

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“…Ubiquitylation of securin and Clb5 by APC/C Cdc20 is more processive than that with APC/C Cdh1 , while Hsl1 is more processively modified by APC/C Cdh1 (ref 19 ).…”

Section: Discussionmentioning

confidence: 99%

“…1b), a late mitotic substrate that is targeted primarily by APC/C Cdh1 in vivo 29 . The Hsl1 D box is known to have an ideal consensus sequence that binds tightly to APC/C Cdh1 , resulting in highly processive modification 19,30 . We found that the Hsl1 D box binds the Cdh1 WD40 domain with a dissociation constant (KD) of 4.0 µM (Fig.…”

Section: Analysis Of Degron Affinity By Ensemble Biochemistrymentioning

confidence: 99%

“…This order is likely to be achieved in part by selectivity of the activators for different substrates. Destruction of securin and a small number of other early substrates depends on Cdc20, whereas numerous later substrates, degraded in late mitosis and G1, are targeted specifically by Cdh1 19,21 . There is some evidence for activator-specific D-box sequences, as well as evidence that the KEN box has a preference for Cdh1 12 .…”

Section: Introductionmentioning

confidence: 99%

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Single-molecule analysis of specificity and multivalency in binding of short linear substrate motifs to the APC/C

Hartooni

Sung

Jain

et al. 2021

Preprint

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Robust regulatory signals in the cell often depend on interactions between short linear motifs (SLiMs) and globular proteins. Many of these interactions are poorly characterized because the binding proteins cannot be produced in the amounts needed for traditional methods. To address this problem, we developed a single-molecule off-rate (SMOR) assay based on microscopy of fluorescent ligand binding to immobilized protein partners. We used it to characterize substrate binding to the Anaphase-Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that triggers chromosome segregation. We find that SLiMs in APC/C substrates (the D box and KEN box) display distinct affinities and specificities for the substrate-binding subunits of the APC/C, and we show that multiple SLiMs in a substrate generate a high-affinity multivalent interaction. The remarkably adaptable substrate-binding mechanisms of the APC/C have the potential to govern the order of substrate destruction in mitosis.

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“…An additional study by Mizrak and Morgan (2019) implicated binding of the APC/C to polyanions, including nucleic acid polymers which are components of nucleosomes, as a mechanism to regulate the dissociation of CDC20 and CDH1 from the APC/C. Using lysates from Saccharomyces cerevisiae to perform in vitro experiments, they show that single-stranded DNA and RNA of about 75 base pairs, as well as polyphosphate species, promote the dissociation of CDC20 and CDH1 from the APC/C.…”

Section: Apc/c Regulates Chromatinmentioning

confidence: 99%

Intricate Regulatory Mechanisms of the Anaphase-Promoting Complex/Cyclosome and Its Role in Chromatin Regulation

Bodrug

Welsh

Hinkle

et al. 2021

Front. Cell Dev. Biol.

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The ubiquitin (Ub)-proteasome system is vital to nearly every biological process in eukaryotes. Specifically, the conjugation of Ub to target proteins by Ub ligases, such as the Anaphase-Promoting Complex/Cyclosome (APC/C), is paramount for cell cycle transitions as it leads to the irreversible destruction of cell cycle regulators by the proteasome. Through this activity, the RING Ub ligase APC/C governs mitosis, G1, and numerous aspects of neurobiology. Pioneering cryo-EM, biochemical reconstitution, and cell-based studies have illuminated many aspects of the conformational dynamics of this large, multi-subunit complex and the sophisticated regulation of APC/C function. More recent studies have revealed new mechanisms that selectively dictate APC/C activity and explore additional pathways that are controlled by APC/C-mediated ubiquitination, including an intimate relationship with chromatin regulation. These tasks go beyond the traditional cell cycle role historically ascribed to the APC/C. Here, we review these novel findings, examine the mechanistic implications of APC/C regulation, and discuss the role of the APC/C in previously unappreciated signaling pathways.

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Polyanions provide selective control of APC/C interactions with the activator subunit

Cited by 11 publications

References 61 publications

In vivo reconstitution finds multivalent RNA–RNA interactions as drivers of mesh-like condensates

In vivo reconstitution finds multivalent RNA–RNA interactions as drivers of mesh-like condensates

Single-molecule analysis of specificity and multivalency in binding of short linear substrate motifs to the APC/C

Intricate Regulatory Mechanisms of the Anaphase-Promoting Complex/Cyclosome and Its Role in Chromatin Regulation

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