Targeted delivery of nitric oxide via a ‘bump-and-hole’-based enzyme–prodrug pair

December 31st, 2018 by Jingli Hou

Targeted delivery of nitric oxide via a ‘bump-and-hole’-based enzyme–prodrug pair

Targeted delivery of nitric oxide via a ‘bump-and-hole’-based enzyme–prodrug pair, Published online: 31 December 2018; doi:10.1038/s41589-018-0190-5

A NO delivery system that depends on the hydrolysis of an alkyl-galactose-conjugated NO prodrug by an engineered galactosidase developed using a ‘bump-and-hole’ strategy enabled targeted delivery of NO to specific tissues.
  • Posted in Nat Chem Biol, Publications
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Post-transcriptional regulation of the Pseudomonas aeruginosa heme assimilation system (Has) fine-tunes extracellular heme sensing [Gene Regulation]

December 28th, 2018 by Alecia T. Dent, Susana Mourino, Weiliang Huang, Angela Wilks

Pseudomonas aeruginosa is an opportunistic pathogen that utilizes heme as a primary iron source within the host. Extracellular heme is sensed via a heme assimilation system (has) that encodes an extra cytoplasmic function (ECF) σ factor system. Herein, using has deletion mutants, qPCR analyses, and immunoblotting, we show that the activation of the σ factor HasI requires heme release from the hemophore HasAp to the outer membrane receptor HasR. Using RT-PCR and 5’-RACE, we observed that following transcriptional activation of the co-transcribed hasRAp, it is further processed into specific mRNAs varying in stability. We noted that the processing and variation in stability of the hasAp and hasR mRNAs in response to heme provides a mechanism for differential expression from co-transcribed genes. The multiple layers of post-transcriptional regulation of the ECF signaling cascade, including the previously reported post-transcriptional regulation of HasAp by the heme metabolites biliverdin IXβ and IXδ, allows fine tuning of the cell surface signaling system in response to extracellular heme levels. We hypothesize that the complex post-transcriptional regulation of the Has system provides P. aeruginosa an advantage in colonizing a variety of physiological niches in the host.
  • Posted in Journal of Biological Chemistry, Publications
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Fall 2018 Newsletter Released

December 28th, 2018 by pthomas2

The fall newsletter was just released. BIOL members should have received it in their email. You can find the newsletter here.

Publisher Correction: Shared strategies for β-lactam catabolism in the soil microbiome

December 27th, 2018 by Terence S. Crofts

Publisher Correction: Shared strategies for β-lactam catabolism in the soil microbiome

Publisher Correction: Shared strategies for β-lactam catabolism in the soil microbiome, Published online: 27 December 2018; doi:10.1038/s41589-018-0208-z

Publisher Correction: Shared strategies for β-lactam catabolism in the soil microbiome
  • Posted in Nat Chem Biol, Publications
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Friend or foe — post-translational modifications as regulators of phase separation and RNP granule dynamics [Molecular Bases of Disease]

December 26th, 2018 by Mario Hofweber, Dorothee Dormann

Ribonucleoprotein (RNP) granules are membrane-less organelles consisting of RNA-binding proteins (RBPs) and RNA. RNA granules form through liquid–liquid phase separation (LLPS), whereby weak promiscuous interactions among RBPs and/or RNAs create a dense network of interacting macromolecules and drive the phase separation. Post-translational modifications (PTMs) of RBPs have emerged as important regulators of LLPS and RNP granule dynamics, as they can directly weaken or enhance the multivalent interactions between phase-separating macromolecules or can recruit or exclude certain macromolecules into or from condensates. Here, we review recent insights into how PTMs regulate phase separation and RNP granule dynamics, in particular arginine (R)-methylation and phosphorylation. We discuss how these PTMs regulate the phase behavior of prototypical RBPs and how, as “friend or foe”, they might influence the assembly, disassembly, or material properties of cellular RNP granules, such as stress granules or amyloid-like condensates. We particularly highlight how PTMs control the phase separation and aggregation behavior of disease-linked RBPs. We also review how disruptions of PTMs might be involved in aberrant phase transitions and the formation of amyloid-like protein aggregates as observed in neurodegenerative diseases.

[ASAP] Tuning Protein Diffusivity with Membrane Tethers

December 24th, 2018 by David Mörsdorf, Patrick Müller

TOC Graphic

Biochemistry
DOI: 10.1021/acs.biochem.8b01150

[ASAP] Response to “Selective PKCd Inhibitor B106 Elicits Uveal Melanoma Growth Inhibitory Effects Independent of Activated PKC Isoforms”

December 21st, 2018 by Douglas V. Faller

ACS Chemical Biology
DOI: 10.1021/acschembio.8b00959
  • Posted in ACS Chemical Biology, Publications
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Publisher Correction: Crystal structure of misoprostol bound to the labor inducer prostaglandin E<sub>2</sub> receptor

December 20th, 2018 by Martin Audet

Publisher Correction: Crystal structure of misoprostol bound to the labor inducer prostaglandin E2 receptor

Publisher Correction: Crystal structure of misoprostol bound to the labor inducer prostaglandin E<sub>2</sub> receptor, Published online: 20 December 2018; doi:10.1038/s41589-018-0214-1

Publisher Correction: Crystal structure of misoprostol bound to the labor inducer prostaglandin E2 receptor
  • Posted in Nat Chem Biol, Publications
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Nrf1-mediated transcriptional regulation of the proteasome requires a functional TIP60 complex [Protein Synthesis and Degradation]

December 17th, 2018 by Janakiram R Vangala, Senthil K Radhakrishnan

Inhibition of the proteasome leads to proteotoxic stress which is characterized by the buildup of ubiquitinated proteins that cannot be degraded properly. The transcription factor Nrf1 (also called NFE2L1) counteracts proteotoxic stress by inducing transcription of proteasome subunit genes resulting in the restoration of proteasome activity. Further understanding of the Nrf1 pathway is therefore of interest in both neurodegeneration, where proteasome activity could be enhanced, and cancer, where suppression of this pathway could potentiate the cell-killing effect mediated by proteasome inhibitor drugs. Here, to identify novel regulators of Nrf1, we performed an RNA interference screen in an engineered cell line reporting on Nrf1 transcriptional activity. In addition to validating known regulators, we discovered that the AAA+ ATPase RUVBL1 is necessary for Nrf1’s transcriptional activity. Given that RUVBL1 is part of different multi-subunit complexes that play key roles in transcription, we dissected this phenomenon further and found that the TIP60 chromatin regulatory complex is essential for Nrf1-dependent transcription of proteasome genes. Consistent with these observations, Nrf1, RUVBL1, and TIP60 proteins were co-recruited to the promoter regions of proteasome genes after proteasome inhibitor treatments. More importantly, depletion of RUVBL1 or TIP60 in various cancer cells sensitized them to cell death induced by proteasome inhibition. Overall, our study provides a framework for manipulating the TIP60-Nrf1 axis to alter proteasome function in various human diseases including cancer.

Metalloprotein switches that display chemical-dependent electron transfer in cells

December 17th, 2018 by Joshua T. Atkinson

Metalloprotein switches that display chemical-dependent electron transfer in cells

Metalloprotein switches that display chemical-dependent electron transfer in cells, Published online: 17 December 2018; doi:10.1038/s41589-018-0192-3

Designed split ferredoxins, fused to protein fragments that associate under certain conditions such as the presence of rapamycin, enable transcriptional and post-translational control over electron transfer in Escherichia coli cells and lysates.
  • Posted in Nat Chem Biol, Publications
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