The 20S as a stand-alone proteasome in cells can degrade the ubiquitin tag

Sahu, Indrajit; Mali, Sachitanand M.; Sulkshane, Prasad; Xu, Cong; Rozenberg, Andrey; Morag, Roni; Sahoo, Manisha Priyadarsini; Singh, Sumeet K.; Ding, Zhanyu; Wang, Yifan; Day, Sharleen; Yao, Cong; Kleifeld, Oded; Brik, Ashraf; Glickman, Michael H.

doi:10.1038/s41467-021-26427-0

Cited by 76 publications

(86 citation statements)

References 98 publications

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“…10h-o). Recent data suggest that the free 20S CP can degrade substrate-conjugated ubiquitin 71 , which might be facilitated by ubiquitin binding to the α-ring.…”

Section: Resultsmentioning

confidence: 99%

Hidden dynamics of proteasome autoregulation discovered by cryo-EM data-driven deep learning

Zhang

Wang

et al. 2020

Preprint

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The 2.5-MDa 26S proteasome maintains proteostasis and regulates myriad cellular processes1. How polyubiquitylated substrate interactions regulate proteasome activity is not understood1,2. Here we introduce a deep manifold learning framework, named AlphaCryo4D, which enables atomic-level cryogenic electron microscopy (cryo-EM) reconstructions of nonequilibrium conformational continuum and reconstitutes ‘hidden’ dynamics of proteasome autoregulation in the act of substrate degradation. AlphaCryo4D integrates 3D deep residual learning3 with manifold embedding4 of free-energy landscapes5, which directs 3D clustering via an energy-based particle-voting algorithm. In blind assessments using simulated heterogeneous cryo-EM datasets, AlphaCryo4D achieved 3D classification accuracy three times that of conventional methods6–9 and reconstructed continuous conformational changes of a 130-kDa protein at sub-3-Å resolution. By using AlphaCryo4D to analyze a single experimental cryo-EM dataset2, we identified 64 conformers of the substrate-bound human 26S proteasome, revealing conformational entanglement of two regulatory particles in the doubly capped holoenzymes and their energetic differences with singly capped ones. Novel ubiquitin-binding sites are discovered on the RPN2, RPN10 and α5 subunits to remodel polyubiquitin chains for deubiquitylation and recycle. Importantly, AlphaCryo4D choreographs single-nucleotide-exchange dynamics of proteasomal AAA-ATPase motor during translocation initiation, which upregulates proteolytic activity by allosterically promoting nucleophilic attack. Our systemic analysis illuminates a grand hierarchical allostery for proteasome autoregulation.

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“…10h-o). Recent data suggest that the free 20S CP can degrade substrate-conjugated ubiquitin 71 , which might be facilitated by ubiquitin binding to the α-ring.…”

Section: Resultsmentioning

confidence: 99%

Hidden dynamics of proteasome autoregulation discovered by cryo-EM data-driven deep learning

Zhang

Wang

et al. 2020

Preprint

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“…However, if the NMP complex also contained auxiliary factors yet to be identified, it might recognize and process folded protein substrates as well. On the other hand, the recent discovery that the 20S CP can by itself degrade ubiquitinated proteins [ 153 ] also implies that NMPs may have a broader range of substrates. A following question is the molecular composition and regulatory mechanisms of the NMPs.…”

Section: Proteasomes At the Membranesmentioning

confidence: 99%

Localized Proteasomal Degradation: From the Nucleus to Cell Periphery

Guo

2022

Biomolecules

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The proteasome is responsible for selective degradation of most cellular proteins. Abundantly present in the cell, proteasomes not only diffuse in the cytoplasm and the nucleus but also associate with the chromatin, cytoskeleton, various membranes and membraneless organelles/condensates. How and why the proteasome gets to these specific subcellular compartments remains poorly understood, although increasing evidence supports the hypothesis that intracellular localization may have profound impacts on the activity, substrate accessibility and stability/integrity of the proteasome. In this short review, I summarize recent advances on the functions, regulations and targeting mechanisms of proteasomes, especially those localized to the nuclear condensates and membrane structures of the cell, and I discuss the biological significance thereof in mediating compartmentalized protein degradation.

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“…It is estimated that more than 20% of proteins in mammalian cells are degraded by the 20S proteasomes ( Baugh et al, 2009 ). The 20S proteasomes recognized damage proteins through specific degradation signals such as multi-ubiquitin chain tag ( Sahu et al, 2021 ). For a protein to be tagged for degradation, a series of reaction was carried out by E1 (ubiquitin-activating), E2 (ubiquitin-conjugating), and E3 (ubiquitin-ligating) enzymes to create a ubiquitin tag that consist of at least 4 ubiquitin molecules.…”

Section: Effects Of Thymoquinone On Signaling Mechanisms Of Ocular Ne...mentioning

confidence: 99%

Thymoquinone in Ocular Neurodegeneration: Modulation of Pathological Mechanisms via Multiple Pathways

Mahmud

Paraoan

Khaliddin

et al. 2022

Front. Cell. Neurosci.

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Thymoquinone is a naturally occurring compound and is the major component of Nigella sativa, also known as black seed or black cumin. For centuries thymoquinone has been used especially in the Middle East traditionally to treat wounds, asthma, allergies, fever, headache, cough, hypertension, and diabetes. Studies have suggested beneficial effects of thymoquinone to be attributed to its antioxidant, antibacterial, anti-oxidative stress, anti-inflammatory, and neuroprotective properties. Recently, there has been a surge of interest in thymoquinone as a treatment for neurodegeneration in the brain, such as that seen in Alzheimer’s (AD) and Parkinson’s diseases (PD). In vitro and in vivo studies on animal models of AD and PD suggest the main neuroprotective mechanisms are based on the anti-inflammatory and anti-oxidative properties of thymoquinone. Neurodegenerative conditions of the eye, such as Age-related Macular Degeneration (AMD) and glaucoma share at least in part similar mechanisms of neuronal cell death with those occurring in AD and PD. This review aims to summarize and critically analyze the evidence to date of the effects and potential neuroprotective actions of thymoquinone in the eye and ocular neurodegenerations.

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The 20S as a stand-alone proteasome in cells can degrade the ubiquitin tag

Cited by 76 publications

References 98 publications

Hidden dynamics of proteasome autoregulation discovered by cryo-EM data-driven deep learning

Hidden dynamics of proteasome autoregulation discovered by cryo-EM data-driven deep learning

Localized Proteasomal Degradation: From the Nucleus to Cell Periphery

Thymoquinone in Ocular Neurodegeneration: Modulation of Pathological Mechanisms via Multiple Pathways

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