EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction

Zhao, Jing; Blayney, Alan J.; Liu, Xiaorong; Gandy, Lauren; Jin, Weihua; Yan, Lufeng; Ha, Jeung Hoi; Canning, Ashley J.; Connelly, Michael S.; Yang, Chao; Liu, Xinyue; Xiao, Yuanyuan; Cosgrove, Michael S.; Solmaz, Sozanne R.; Zhang, Yingkai; Ban, David; Chen, Jianhan; Loh, Stewart N.; Wang, Qianqian

doi:10.1038/s41467-021-21258-5

Cited by 82 publications

(68 citation statements)

References 82 publications

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“…We thought that these direct effects did not play a primary role in vivo, as indicated by our results that mice with colitis treated by rectal EGCG trended to exacerbate colitis. As the most abundant tea polyphenol in green tea, it was likely that the beneficial effects of EGCG were mediated through more than one mechanism [61,62]. Besides the functional SCFAs, previous studies have revealed that some phenolic metabolites from EGCG degradation may play a critical role, alongside other beneficial activities of EGCG, in reducing intestinal inflammatory diseases [63,64].…”

Section: Discussionmentioning

confidence: 99%

Gut microbiota from green tea polyphenol-dosed mice improves intestinal epithelial homeostasis and ameliorates experimental colitis

et al. 2021

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Background Alteration of the gut microbiota may contribute to the development of inflammatory bowel disease (IBD). Epigallocatechin-3-gallate (EGCG), a major bioactive constituent of green tea, is known to be beneficial in IBD alleviation. However, it is unclear whether the gut microbiota exerts an effect when EGCG attenuates IBD. Results We first explored the effect of oral or rectal EGCG delivery on the DSS-induced murine colitis. Our results revealed that anti-inflammatory effect and colonic barrier integrity were enhanced by oral, but not rectal, EGCG. We observed a distinct EGCG-mediated alteration in the gut microbiome by increasing Akkermansia abundance and butyrate production. Next, we demonstrated that the EGCG pre-supplementation induced similar beneficial outcomes to oral EGCG administration. Prophylactic EGCG attenuated colitis and significantly enriched short-chain fatty acids (SCFAs)-producing bacteria such as Akkermansia and SCFAs production in DSS-induced mice. To validate these discoveries, we performed fecal microbiota transplantation (FMT) and sterile fecal filtrate (SFF) to inoculate DSS-treated mice. Microbiota from EGCG-dosed mice alleviated the colitis over microbiota from control mice and SFF shown by superiorly anti-inflammatory effect and colonic barrier integrity, and also enriched bacteria such as Akkermansia and SCFAs. Collectively, the attenuation of colitis by oral EGCG suggests an intimate involvement of SCFAs-producing bacteria Akkermansia, and SCFAs, which was further demonstrated by prophylaxis and FMT. Conclusions This study provides the first data indicating that oral EGCG ameliorated the colonic inflammation in a gut microbiota-dependent manner. Our findings provide novel insights into EGCG-mediated remission of IBD and EGCG as a potential modulator for gut microbiota to prevent and treat IBD.

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Section: Discussionmentioning

confidence: 99%

Gut microbiota from green tea polyphenol-dosed mice improves intestinal epithelial homeostasis and ameliorates experimental colitis

et al. 2021

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“…SAXS data was collected at the beam line 7A1 at the Cornell High Energy Synchrotron Source (CHESS), with a dual Pilatus 100k detector system (Dectris, Baden, Switzerland), at a single detector position, on July 3, 2019 as described previously 85 . Quartz capillary with a path length of 1.6 mm was used as the sample cell (OD=1.5 mm, wall thickness=10 μm).…”

Section: Methodsmentioning

confidence: 99%

Coil-to-Helix Transition at the Nup358-BicD2 Interface Activates BicD2 for Dynein Recruitment

Gibson

Cui

Ali

et al. 2021

Preprint

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Nup358, a nuclear pore protein, facilitates a nuclear positioning pathway that is essential for brain development. Nup358 binds and activates the auto-inhibited dynein adaptor Bicaudal D2 (BicD2), which in turn recruits and activates the dynein machinery to position the nucleus. The molecular details of the Nup358/BicD2 interaction remain poorly understood. Here, we show that a minimal dimerized Nup358 domain activates dynein/dynactin/BicD2 for processive motility on microtubules. Using nuclear magnetic resonance (NMR) titration and chemical exchange saturation transfer (CEST), a Nup358-helix encompassing residues 2162-2184 was identified, which transitioned from random coil to an alpha-helix upon BicD2-binding and formed the core of the Nup358-BicD2 interface. Mutations in this region of Nup358 decreased the Nup358/BicD2 interaction, resulting in decreased dynein recruitment and impaired motility. BicD2 thus recognizes the cargo adaptor Nup358 though a 'cargo recognition alpha-helix', a structural feature that may stabilize BicD2 in its activated state, promoting activation of dynein motility.

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“…Both works directly showed that REST covered broader conformational spaces for intrinsically disordered regions and led to faster convergence compared to either standard MD or T-REMD simulations. REST simulations have also been successfully integrated with experiments to study how cancer-associated mutations and drug molecules may modulate the disordered ensembles of p53-TAD and Aβ peptides in recent years [118][119][120][121].…”

Section: Collective Variables-free Sampling Methods and Optimizationmentioning

confidence: 99%

Advanced Sampling Methods for Multiscale Simulation of Disordered Proteins and Dynamic Interactions

Gong

Chen

2021

Biomolecules

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Intrinsically disordered proteins (IDPs) are highly prevalent and play important roles in biology and human diseases. It is now also recognized that many IDPs remain dynamic even in specific complexes and functional assemblies. Computer simulations are essential for deriving a molecular description of the disordered protein ensembles and dynamic interactions for a mechanistic understanding of IDPs in biology, diseases, and therapeutics. Here, we provide an in-depth review of recent advances in the multi-scale simulation of disordered protein states, with a particular emphasis on the development and application of advanced sampling techniques for studying IDPs. These techniques are critical for adequate sampling of the manifold functionally relevant conformational spaces of IDPs. Together with dramatically improved protein force fields, these advanced simulation approaches have achieved substantial success and demonstrated significant promise towards the quantitative and predictive modeling of IDPs and their dynamic interactions. We will also discuss important challenges remaining in the atomistic simulation of larger systems and how various coarse-grained approaches may help to bridge the remaining gaps in the accessible time- and length-scales of IDP simulations.

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EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction

Cited by 82 publications

References 82 publications

Gut microbiota from green tea polyphenol-dosed mice improves intestinal epithelial homeostasis and ameliorates experimental colitis

Gut microbiota from green tea polyphenol-dosed mice improves intestinal epithelial homeostasis and ameliorates experimental colitis

Coil-to-Helix Transition at the Nup358-BicD2 Interface Activates BicD2 for Dynein Recruitment

Advanced Sampling Methods for Multiscale Simulation of Disordered Proteins and Dynamic Interactions

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