Computationally modeling mammalian succinate dehydrogenase kinetics identifies the origins and primary determinants of ROS production [Bioenergetics]
In this study, we showed the importance of analyzing enzyme kinetics and associated side reactions in a consistent, quantitative, and biophysically detailed manner using a diverse set of experimental data to interpret and explain experimental observations from a unified perspective. (Source: Journal of Biological Chemistry)
Source: Journal of Biological Chemistry - November 6, 2020 Category: Chemistry Authors: Neeraj Manhas, Quynh V. Duong, Pilhwa Lee, Joshua D. Richardson, John D. Robertson, Michael A. Moxley, Jason N. Bazil Tags: Computational Biology Source Type: research
Asp22 drives the protonation state of the Staphylococcus epidermidis glucose/H+ symporter [Membrane Biology]
The Staphylococcus epidermidis glucose/H+ symporter (GlcPSe) is a membrane transporter highly specific for glucose and a homolog of the human glucose transporters (GLUT, SLC2 family). Most GLUTs and their bacterial counterparts differ in the transport mechanism, adopting uniport and sugar/H+ symport, respectively. Unlike other bacterial GLUT homologs (for example, XylE), GlcPSe has a loose H+/sugar coupling. Asp22 is part of the proton-binding site of GlcPSe and crucial for the glucose/H+ co-transport mechanism. To determine how pH variations affect the proton site and the transporter, we performed surface-enhanced IR abso...
Source: Journal of Biological Chemistry - November 6, 2020 Category: Chemistry Authors: Ana Filipa Santos Seica, Cristina V. Iancu, Benedikt Pfeilschifter, M. Gregor Madej, Jun-Yong Choe, Petra Hellwig Tags: Molecular Biophysics Source Type: research
Inhibitory effect of UDP-glucose on cAMP generation and insulin secretion [Signal Transduction]
Type-2 diabetes (T2D) is a global disease caused by the inability of pancreatic β-cells to secrete adequate insulin. However, the molecular mechanisms underlying the failure of β-cells to respond to glucose in T2D remains unknown. Here, we investigated the relative contribution of UDP-glucose (UDP-G), a P2Y14-specific agonist, in the regulation of insulin release using human isolated pancreatic islets and INS-1 cells. P2Y14 was expressed in both human and rodent pancreatic β-cells. Dose-dependent activation of P2Y14 by UDP-G suppressed glucose-stimulated insulin secretion (GSIS) and knockdown of P2Y14 abolished the UDP-...
Source: Journal of Biological Chemistry - November 6, 2020 Category: Chemistry Authors: Fariborz Parandeh, Stefan Amisten, Gaurav Verma, Israa Mohammed Al–Amily, Pontus Duner, Albert Salehi Tags: Molecular Bases of Disease Source Type: research
Zymogen and activated protein C have similar structural architecture [Molecular Biophysics]
Activated protein C is a trypsin-like protease with anticoagulant and cytoprotective properties that is generated by thrombin from the zymogen precursor protein C in a reaction greatly accelerated by the cofactor thrombomodulin. The molecular details of this activation remain elusive due to the lack of structural information. We now fill this gap by providing information on the overall structural organization of these proteins using single molecule FRET and small angle X-ray scattering. Under physiological conditions, both zymogen and protease adopt a conformation with all domains vertically aligned along an axis 76 Å lon...
Source: Journal of Biological Chemistry - November 6, 2020 Category: Chemistry Authors: Bosko M. Stojanovski, Leslie A. Pelc, Xiaobing Zuo, Enrico Di Cera Tags: Enzymology Source Type: research
Bioenergetic defects in muscle fibers of RYR1 mutant knock-in mice associated with malignant hyperthermia [Metabolism]
Mutations in the skeletal muscle ryanodine receptor gene (RYR1) can cause susceptibility to malignant hyperthermia (MH), a potentially lethal genetic condition triggered by volatile anesthetics. MH is associated with hypermetabolism, which has directed research interest into oxidative phosphorylation and muscle bioenergetics. The most common cause of MH in the United Kingdom is the c.7300G>A RYR1 variant, which is present in ∼16% of MH families. Our study focuses on the MH susceptible G2435R-RYR1 knock-in mouse model, which is the murine equivalent of the human c.7300G>A genotype. Using a combination of transcriptomics, ...
Source: Journal of Biological Chemistry - November 6, 2020 Category: Chemistry Authors: Leon Chang, Xiaochen Liu, Christine P. Diggle, John P. Boyle, Philip M. Hopkins, Marie-Anne Shaw, Paul D. Allen Tags: Bioenergetics Source Type: research
Nuclear receptor phosphorylation in xenobiotic signal transduction [Signal Transduction]
Nuclear pregnane X receptor (PXR, NR1I2) and constitutive active/androstane receptor (CAR, NR1I3) are nuclear receptors characterized in 1998 by their capability to respond to xenobiotics and activate cytochrome P450 (CYP) genes. An anti-epileptic drug, phenobarbital (PB), activates CAR and its target CYP2B genes, whereas PXR is activated by drugs such as rifampicin and statins for the CYP3A genes. Inevitably, both nuclear receptors have been investigated as ligand-activated nuclear receptors by identifying and characterizing xenobiotics and therapeutics that directly bind CAR and/or PXR to activate them. However, PB, whic...
Source: Journal of Biological Chemistry - November 6, 2020 Category: Chemistry Authors: Masahiko Negishi, Kaoru Kobayashi, Tsutomu Sakuma, Tatsuya Sueyoshi Tags: JBC Reviews Source Type: research
Exosites expedite blood coagulation [Molecular Bases of Disease]
A careful balance between active-site and exosite contributions is critically important for the specificity of many proteases, but this balance is not yet defined for some of the serine proteases that serve as coagulation factors. Basavaraj and Krishnaswamy have closed an important gap in our knowledge of coagulation factor X activation by the intrinsic Xase complex by showing that exosite binding plays a critical role in this process, which they describe as a “dock and lock.” This finding not only significantly enhances our understanding of this step in the coagulation cascade and highlights parallels with the prothro...
Source: Journal of Biological Chemistry - November 6, 2020 Category: Chemistry Authors: Maria Luiza Vilela Oliva, Ingrid Dreveny, Jonas Emsley Tags: Editors ' Picks Highlights Source Type: research
Exosite binding drives substrate affinity for the activation of coagulation factor X by the intrinsic Xase complex [Protein Structure and Folding]
Factor X activation by the intrinsic Xase complex, composed of factor IXa bound to factor VIIIa on membranes, is essential for the amplified blood coagulation response. The biological significance of this step is evident from bleeding arising from deficiencies in factors VIIIa or IXa in hemophilia. Here, we assess the mechanism(s) that enforce the distinctive specificity of intrinsic Xase for its biological substrate. Active-site function of IXa was assessed with a tripeptidyl substrate (PF-3688). The reversible S1 site binder, 4-aminobenzamidine (pAB), acted as a classical competitive inhibitor of PF-3688 cleavage by Xase...
Source: Journal of Biological Chemistry - November 6, 2020 Category: Chemistry Authors: Manjunath Goolyam Basavaraj, Sriram Krishnaswamy Tags: Editors ' Picks Source Type: research
HIV fusion: Catch me if you can [Microbiology]
The penetration of enveloped viruses into target cells requires the fusion of the lipid envelope of their virions with the host lipid membrane though a stepwise and highly sophisticated process. However, the intermediate steps in this process have seldom been visualized due to their rarity and rapidity. Here, using cryo-electron tomography, TIRF microscopy, and cell membrane–derived vesicles called blebs, Ward et al. visualize intermediates of the HIV-cell membrane fusion process and demonstrate how Serinc proteins prevent full fusion by interfering with this process. (Source: Journal of Biological Chemistry)
Source: Journal of Biological Chemistry - November 6, 2020 Category: Chemistry Authors: Solene Denolly, Francois–Loic Cosset Tags: Editors ' Picks Highlights Source Type: research
HIV-cell membrane fusion intermediates are restricted by Serincs as revealed by cryo-electron and TIRF microscopy [Microbiology]
To enter a cell and establish infection, HIV must first fuse its lipid envelope with the host cell plasma membrane. Whereas the process of HIV membrane fusion can be tracked by fluorescence microscopy, the 3D configuration of proteins and lipids at intermediate steps can only be resolved with cryo-electron tomography (cryoET). However, cryoET of whole cells is technically difficult. To overcome this problem, we have adapted giant plasma membrane vesicles (or blebs) from native cell membranes expressing appropriate receptors as targets for fusion with HIV envelope glycoprotein-expressing pseudovirus particles with and witho...
Source: Journal of Biological Chemistry - November 6, 2020 Category: Chemistry Authors: Amanda E. Ward, Volker Kiessling, Owen Pornillos, Judith M. White, Barbie K. Ganser-Pornillos, Lukas K. Tamm Tags: Editors ' Picks Source Type: research
Sphingosine prevents binding of SARS-CoV-2 spike to its cellular receptor ACE2 [Molecular Bases of Disease]
Sphingosine has been shown to prevent and eliminate bacterial infections of the respiratory tract, but it is unknown whether sphingosine can be also employed to prevent viral infections. To test this hypothesis, we analyzed whether sphingosine regulates the infection of cultured and freshly isolated ex vivo human epithelial cells with pseudoviral particles expressing SARS–CoV-2 spike (pp-VSV–SARS–CoV-2 spike) that served as a bona fide system mimicking SARS–CoV-2 infection. We demonstrate that exogenously applied sphingosine suspended in 0.9% NaCl prevents cellular infection with pp-SARS–CoV-2 spike. Pretreatment...
Source: Journal of Biological Chemistry - November 6, 2020 Category: Chemistry Authors: Michael J. Edwards, Katrin Anne Becker, Barbara Gripp, Markus Hoffmann, Simone Keitsch, Barbara Wilker, Matthias Soddemann, Anne Gulbins, Elisa Carpinteiro, Sameer H. Patel, Gregory C. Wilson, Stefan Pohlmann, Silke Walter, Klaus Fassbender, Syed A. Ahmad Tags: Editors ' Picks Source Type: research
We mark the passing of two giants of JBC [Editorials]
JBC had editors-in-chief before Herbert Tabor, and others, like myself, will follow. But no one will ever match the incredible impact and melding of identity between the journal and the editor achieved by Tabor. His legacy at JBC has been captured and saluted by many; we list several links to these homages below. Here we will simply say that JBC is, to many, nearly synonymous with Herb Tabor. Over critical decades in the growth of JBC, he guided its vision, shaped key decisions such as becoming an on-line journal before others dreamed of it, and led with a quiet but firm clarity that all respected. More than forty years of...
Source: Journal of Biological Chemistry - October 30, 2020 Category: Chemistry Authors: Lila M. Gierasch Tags: Editorials Source Type: research
Correction: Phase separation drives decision making in cell division. [Additions and Corrections]
VOLUME 295 (2020) PAGES 13419–13431The second author Xu Liu was inadvertently removed from the author list. (Source: Journal of Biological Chemistry)
Source: Journal of Biological Chemistry - October 30, 2020 Category: Chemistry Authors: Xing Liu, Haowei Wang, Zhen Dou, Ke Ruan, Donald L. Hill, Lin Li, Yunyu Shi, Xuebiao Yao Tags: Additions and Corrections Source Type: research
Structure, function, and inhibitor targeting of HIV-1 Nef-effector kinase complexes [Protein Structure and Folding]
Antiretroviral therapy has revolutionized the treatment of AIDS, turning a deadly disease into a manageable chronic condition. Life-long treatment is required because existing drugs do not eradicate HIV-infected cells. The emergence of drug-resistant viral strains and uncertain vaccine prospects highlight the pressing need for new therapeutic approaches with the potential to clear the virus. The HIV-1 accessory protein Nef is essential for viral pathogenesis, making it a promising target for antiretroviral drug discovery. Nef enhances viral replication and promotes immune escape of HIV-infected cells but lacks intrinsic en...
Source: Journal of Biological Chemistry - October 30, 2020 Category: Chemistry Authors: Ryan P. Staudt, John J. Alvarado, Lori A. Emert-Sedlak, Haibin Shi, Sherry T. Shu, Thomas E. Wales, John R. Engen, Thomas E. Smithgall Tags: JBC Reviews Source Type: research
Redesigning plant cell walls for the biomass-based bioeconomy [Glycobiology and Extracellular Matrices]
Lignocellulosic biomass—the lignin, cellulose, and hemicellulose that comprise major components of the plant cell well—is a sustainable resource that could be utilized in the United States to displace oil consumption from heavy vehicles, planes, and marine-going vessels and commodity chemicals. Biomass-derived sugars can also be supplied for microbial fermentative processing to fuels and chemicals or chemically deoxygenated to hydrocarbons. However, the economic value of biomass might be amplified by diversifying the range of target products that are synthesized in living plants. Genetic engineering of lignocellulosic ...
Source: Journal of Biological Chemistry - October 30, 2020 Category: Chemistry Authors: Nicholas C. Carpita, Maureen C. McCann Tags: JBC Reviews Source Type: research
