Functional selectivity of GPCR-directed drug action through location bias

May 29th, 2017 by Roshanak Irannejad

Nature Chemical Biology 13, 799 (2017). doi:10.1038/nchembio.2389

Authors: Roshanak Irannejad, Veronica Pessino, Delphine Mika, Bo Huang, Philip B Wedegaertner, Marco Conti & Mark von Zastrow

  • Posted in Nat Chem Biol, Publications
  • Comments Off on Functional selectivity of GPCR-directed drug action through location bias

Deamidation Slows Curli Amyloid-Protein Aggregation

May 26th, 2017 by Hanliu Wang, Qin Shu, Carl Frieden and Michael L. Gross

TOC Graphic

Biochemistry
DOI: 10.1021/acs.biochem.7b00241

Endoplasmic Reticulum Stress-induced Degradation of DNAJB12 Stimulates BOK Accumulation and Primes Cancer Cells for Apoptosis [Cell Biology]

May 23rd, 2017 by Pattarawut Sopha, Hong Yu Ren, Diane E. Grove, Douglas M Cyr

DNAJB12 (JB12) is an endoplasmic reticulum (ER)-associated Hsp40 family protein that recruits Hsp70 to the ER surface to coordinate the function of ER-associated and cytosolic chaperone systems in protein quality control. Hsp70 is stress inducible, but paradoxically, we report here that JB12 was degraded by the proteasome during severe ER stress. Destabilized JB12 was degraded by ER-associated degradation (ERAD) complexes that contained HERP, Sel1L, and gp78. JB12 was the only ER-associated chaperone that was destabilized by reductive stress. JB12 knockdown by siRNA led to the induction of Caspase processing, but not the unfolded protein response. ER stress-induced apoptosis is regulated by the highly labile and ER associated BCL-2 family member BOK, which is controlled at the level of protein stability by ERAD components. We found that JB12 was required in Huh-7 liver cancer cells to maintain BOK at low levels and BOK was detected in complexes with JB12 and gp78. Depletion of JB12 during reductive stress or by shRNA from Huh-7 cells was associated with accumulation of BOK, and activation of Caspase 3, 7, and 9. Absence of JB12 sensitized Huh-7 to death caused by proteotoxic agents and the proapoptotic chemotherapeutic LCL-161. In summary, JB12 is a stress sensitive Hsp40 whose degradation during severe ER stress provides a mechanism to promote BOK accumulation and induction of apoptosis.

Celiac Disease: Lessons for and from Chemical Biology

May 22nd, 2017 by Chaitan Khosla

TOC Graphic

ACS Chemical Biology
DOI: 10.1021/acschembio.6b01155

Induced Fit Is a Special Case of Conformational Selection

May 22nd, 2017 by Pradipta Chakraborty and Enrico Di Cera

TOC Graphic

Biochemistry
DOI: 10.1021/acs.biochem.7b00340

Recognition of EGF-like domains by the Notch-modifying O-fucosyltransferase POFUT1

May 22nd, 2017 by Zhijie Li

Nature Chemical Biology 13, 757 (2017). doi:10.1038/nchembio.2381

Authors: Zhijie Li, Kristina Han, John E Pak, Malathy Satkunarajah, Dongxia Zhou & James M Rini

  • Posted in Nat Chem Biol, Publications
  • Comments Off on Recognition of EGF-like domains by the Notch-modifying O-fucosyltransferase POFUT1

A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor

May 22nd, 2017 by Marco P Licciardello

Nature Chemical Biology 13, 771 (2017). doi:10.1038/nchembio.2382

Authors: Marco P Licciardello, Anna Ringler, Patrick Markt, Freya Klepsch, Charles-Hugues Lardeau, Sara Sdelci, Erika Schirghuber, André C Müller, Michael Caldera, Anja Wagner, Rebecca Herzog, Thomas Penz, Michael Schuster, Bernd Boidol, Gerhard Dürnberger, Yasin Folkvaljon, Pär Stattin, Vladimir Ivanov, Jacques Colinge, Christoph Bock, Klaus Kratochwill, Jörg Menche, Keiryn L Bennett & Stefan Kubicek

  • Posted in Nat Chem Biol, Publications
  • Comments Off on A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor

Engineering protein stability with atomic precision in a monomeric miniprotein

May 22nd, 2017 by Emily G Baker

Nature Chemical Biology 13, 764 (2017). doi:10.1038/nchembio.2380

Authors: Emily G Baker, Christopher Williams, Kieran L Hudson, Gail J Bartlett, Jack W Heal, Kathryn L Porter Goff, Richard B Sessions, Matthew P Crump & Derek N Woolfson

  • Posted in Nat Chem Biol, Publications
  • Comments Off on Engineering protein stability with atomic precision in a monomeric miniprotein

Engineering RGB color vision into Escherichia coli

May 22nd, 2017 by Jesus Fernandez-Rodriguez

Nature Chemical Biology 13, 706 (2017). doi:10.1038/nchembio.2390

Authors: Jesus Fernandez-Rodriguez, Felix Moser, Miryoung Song & Christopher A Voigt

Optogenetic tools use colored light to rapidly control gene expression in space and time. We designed a genetically encoded system that gives Escherichia coli the ability to distinguish between red, green, and blue (RGB) light and respond by changing gene expression. We use this system to produce 'color photographs' on bacterial culture plates by controlling pigment production and to redirect metabolic flux by expressing CRISPRi guide RNAs.

The sialate O-acetylesterase EstA from gut Bacteroidetes species enables sialidase-mediated cross-species foraging of 9-O-acetylated sialoglycans [Microbiology]

May 19th, 2017 by Lloyd S Robinson, Warren G Lewis, Amanda L Lewis

The gut harbors many symbiotic, commensal, and pathogenic microbes that engage in the breakdown and metabolism of host carbohydrates. Sialic acids are prominent outermost carbohydrates on mucins and protect underlying glycan chains from enzymatic degradation. Sialidases produced by some members of the colonic microbiota have been shown to promote the expansion of several potential pathogens (e.g. Clostridium difficile, Salmonella, Escherichia coli) that do not produce sialidases. O-acetyl ester modifications of sialic acids help resist the action of many sialidases and are found at high levels in the mammalian colon. However, some gut bacteria, in turn, produce sialylate-O-acetyl esterases to remove them. Here we investigated O-acetylation as a shield against the release of sialic acids by Bacteroidetes sialidases and the subsequent utilization of host sialic acids by commensal and pathogenic strains of E. coli. In vitro foraging studies demonstrated that sialidase-dependent E. coli outgrowth on mucin is enabled by Bacteroides EstA, which acts on glycosidically-linked sialylate-O-acety-esterase substrates, particularly at neutral pH. Biochemical studies suggest that spontaneous migration of O-acetyl esters on the side chain of sialic acid, which can occur at colonic pH, may serve as a switch controlling EstA-assisted sialic acid liberation. Specifically, EstA does not act on O-acetyl esters in their initial 7-position. But, following migration to the 9-position, glycans with O-acetyl esters become susceptible to the sequential enzyme action of bacterial esterases and sialidases. Thus, EstA specifically unlocks the nutritive potential of 9-O-acetylated mucus sialic acids for foraging by bacteria that otherwise lack the means to access this potential carbon source.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on The sialate O-acetylesterase EstA from gut Bacteroidetes species enables sialidase-mediated cross-species foraging of 9-O-acetylated sialoglycans [Microbiology]