Structural and functional insight into human O-GlcNAcase

March 27th, 2017 by Christian Roth

Nature Chemical Biology 13, 610 (2017). doi:10.1038/nchembio.2358

Authors: Christian Roth, Sherry Chan, Wendy A Offen, Glyn R Hemsworth, Lianne I Willems, Dustin T King, Vimal Varghese, Robert Britton, David J Vocadlo & Gideon J Davies

O-GlcNAc hydrolase (OGA) removes O-linked N-acetylglucosamine (O-GlcNAc) from a myriad of nucleocytoplasmic proteins. Through co-expression and assembly of OGA fragments, we determined the three-dimensional structure of human OGA, revealing an unusual helix-exchanged dimer that lays a structural foundation for an improved understanding of substrate recognition and regulation of OGA. Structures of OGA in complex with a series of inhibitors define a precise blueprint for the design of inhibitors that have clinical value.

pH regulation in early endosomes and interferon-inducible transmembrane proteins control avian retrovirus fusion [Membrane Biology]

March 24th, 2017 by Tanay M Desai, Mariana Marin, Caleb Mason, Gregory B Melikyan

Enveloped viruses infect host cells by fusing their membranes with those of the host cell, a process mediated by viral glycoproteins upon binding to cognate host receptors or entering into acidic intracellular compartments. Whereas the effect of receptor density on viral infection has been well studied, the role of cell type-specific factors/processes, such as pH regulation, has not been characterized in sufficient detail. Here, we examined the effects of cell-extrinsic factors (buffer environment) and cell-intrinsic factors (interferon-inducible transmembrane proteins, IFITMs), on the pH regulation in early endosomes and on the efficiency of acid-dependent fusion of the Avian Sarcoma and Leukosis Virus, ASLV, with endosomes. First, we found that a modest elevation of external pH can raise the pH in early endosomes in a cell type-dependent manner and thereby delay the acid-induced fusion of endocytosed ASLV. Second, we observed a cell type-dependent delay between the low pH-dependent and temperature-dependent steps of viral fusion, consistent with the delayed enlargement of the fusion pore. Third, ectopic expression of IFITMs, known to potently block influenza virus fusion with late compartments, was found to only partially inhibit ASLV fusion with early endosomes. Interestingly, IFITM expression promoted virus uptake and the acidification of endosomal compartments, resulting in an accelerated fusion rate, when driven by the glycosylphosphatidylinositol-anchored, but not by the transmembrane isoform of the ASLV receptor. Collectively, these results highlight the role of cell-extrinsic and cell-intrinsic factors in regulating the efficiency and kinetics of virus entry and fusion with target cells.

Selective Downregulation of JAK2 and JAK3 by an ATP-Competitive pan-JAK Inhibitor

March 22nd, 2017 by S. Denise Field, Jacob Arkin, Jing Li and Lyn H. Jones

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ACS Chemical Biology
DOI: 10.1021/acschembio.7b00116

Development: Marking the transition

March 22nd, 2017 by Grant Miura

Nature Chemical Biology 13, 343 (2017). doi:10.1038/nchembio.2349

Author: Grant Miura

Fatty acid synthases: Re-engineering biofactories

March 22nd, 2017 by Timm Maier

Nature Chemical Biology 13, 344 (2017). doi:10.1038/nchembio.2338

Author: Timm Maier

Systematically modifying biological assembly lines for the synthesis of novel products remains a challenge. Structural insights and computational modeling have now paved the way for efficient redesigns of giant fatty acid synthases.

Bioconjugation: Methionine’s time to shine

March 22nd, 2017 by Caitlin Deane

Nature Chemical Biology 13, 343 (2017). doi:10.1038/nchembio.2350

Author: Caitlin Deane

Imaging: Luciferase matchmaker

March 22nd, 2017 by Caitlin Deane

Nature Chemical Biology 13, 343 (2017). doi:10.1038/nchembio.2352

Author: Caitlin Deane

Versatile modes of cellular regulation via cyclic dinucleotides

March 22nd, 2017 by Petya Violinova Krasteva

Nature Chemical Biology 13, 350 (2017). doi:10.1038/nchembio.2337

Authors: Petya Violinova Krasteva & Holger Sondermann

Signaling: Spatial regulation of axonal cAMP

March 22nd, 2017 by Pierre Vincent

Nature Chemical Biology 13, 348 (2017). doi:10.1038/nchembio.2339

Authors: Pierre Vincent & Liliana R Castro

In early-stage developing neurons, the cAMP–PKA (protein kinase A) signaling pathway is strongly inhibited. This negative control is later removed, unleashing cAMP–PKA signaling, particularly in distal axonal parts, thus allowing for axonal growth.

Protein folding: Illuminating chaperone activity

March 22nd, 2017 by Danny M Hatters

Nature Chemical Biology 13, 346 (2017). doi:10.1038/nchembio.2332

Author: Danny M Hatters

Pharmacological chaperones are small drugs that stabilize a protein's fold and are being developed to treat diseases arising from protein misfolding. A mathematical framework to model their activity in cells enables insight into their mechanism and capacity to rescue protein foldedness.