Genetic diseases of the Kennedy pathways for membrane synthesis [Molecular Bases of Disease]
The two branches of the Kennedy pathways (CDP-choline and CDP-ethanolamine) are the predominant pathways responsible for the synthesis of the most abundant phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively, in mammalian membranes. Recently, hereditary diseases associated with single gene mutations in the Kennedy pathways have been identified. Interestingly, genetic diseases within the same pathway vary greatly, ranging from muscular dystrophy to spastic paraplegia to a childhood blinding disorder to bone deformations. Indeed, different point mutations in the same gene (PCYT1; CCTα) result in at...
Source: Journal of Biological Chemistry - December 18, 2020 Category: Chemistry Authors: Mahtab Tavasoli, Sarah Lahire, Taryn Reid, Maren Brodovsky, Christopher R. McMaster Tags: JBC Reviews Source Type: research
Antibiotic binding releases autoinhibition of the TipA multidrug-resistance transcriptional regulator [Gene Regulation]
Investigations of bacterial resistance strategies can aid in the development of new antimicrobial drugs as a countermeasure to the increasing worldwide prevalence of bacterial antibiotic resistance. One such strategy involves the TipA class of transcription factors, which constitute minimal autoregulated multidrug resistance (MDR) systems against diverse antibiotics. However, we have insufficient information regarding how antibiotic binding induces transcriptional activation to design molecules that could interfere with this process. To learn more, we determined the crystal structure of SkgA from Caulobacter crescentus as ...
Source: Journal of Biological Chemistry - December 18, 2020 Category: Chemistry Authors: Xuguang Jiang, Linjuan Zhang, Maikun Teng, Xu Li Tags: Protein Structure and Folding Source Type: research
Identification and biochemical characterization of Asp t 36, a new fungal allergen from Aspergillus terreus [Protein Structure and Folding]
Aspergillus terreus is an allergenic fungus, in addition to causing infections in both humans and plants. However, the allergens in this fungus are still unknown, limiting the development of diagnostic and therapeutic strategies. We used a proteomic approach to search for allergens, identifying 16 allergens based on two-dimensional immunoblotting with A. terreus susceptible patient sera. We further characterized triose-phosphate isomerase (Asp t 36), one of the dominant IgE (IgE)-reactive proteins. The gene was cloned and expressed in Escherichia coli. Phylogenetic analysis showed Asp t 36 to be highly conserved with close...
Source: Journal of Biological Chemistry - December 18, 2020 Category: Chemistry Authors: Bijoya Karmakar, Bodhisattwa Saha, Kuladip Jana, Swati Gupta Bhattacharya Tags: Immunology Source Type: research
Biochemical transformation of bacterial lipopolysaccharides by acyloxyacyl hydrolase reduces host injury and promotes recovery [Enzymology]
Animals can sense the presence of microbes in their tissues and mobilize their own defenses by recognizing and responding to conserved microbial structures (often called microbe-associated molecular patterns (MAMPs)). Successful host defenses may kill the invaders, yet the host animal may fail to restore homeostasis if the stimulatory microbial structures are not silenced. Although mice have many mechanisms for limiting their responses to lipopolysaccharide (LPS), a major Gram-negative bacterial MAMP, a highly conserved host lipase is required to extinguish LPS sensing in tissues and restore homeostasis. We review recent p...
Source: Journal of Biological Chemistry - December 18, 2020 Category: Chemistry Authors: Robert S. Munford, Jerrold P. Weiss, Mingfang Lu Tags: JBC Reviews Source Type: research
Clearance of intracellular tau protein from neuronal cells via VAMP8-induced secretion [Cell Biology]
In Alzheimer's disease (AD), tau, a microtubule-associated protein (MAP), becomes hyperphosphorylated, aggregates, and accumulates in the somato-dendritic compartment of neurons. In parallel to its intracellular accumulation in AD, tau is also released in the extracellular space, as revealed by its increased presence in cerebrospinal fluid (CSF). Consistent with this, recent studies, including ours, have reported that neurons secrete tau, and several therapeutic strategies aim to prevent the intracellular tau accumulation. Previously, we reported that late endosomes were implicated in tau secretion. Here, we explore the po...
Source: Journal of Biological Chemistry - December 18, 2020 Category: Chemistry Authors: Julie Pilliod, Alexandre Desȷardins, Camille Pernegre, Helene Jamann, Catherine Larochelle, Edward A. Fon, Nicole Leclerc Tags: Molecular Bases of Disease Source Type: research
A novel method produces native light-harvesting complex II aggregates from the photosynthetic membrane revealing their role in nonphotochemical quenching [Bioenergetics]
Nonphotochemical quenching (NPQ) is a mechanism of regulating light harvesting that protects the photosynthetic apparatus from photodamage by dissipating excess absorbed excitation energy as heat. In higher plants, the major light-harvesting antenna complex (LHCII) of photosystem (PS) II is directly involved in NPQ. The aggregation of LHCII is proposed to be involved in quenching. However, the lack of success in isolating native LHCII aggregates has limited the direct interrogation of this process. The isolation of LHCII in its native state from thylakoid membranes has been problematic because of the use of detergent, whic...
Source: Journal of Biological Chemistry - December 18, 2020 Category: Chemistry Authors: Mahendra K. Shukla, Akimasa Watanabe, Sam Wilson, Vasco Giovagnetti, Ece Imam Moustafa, Jun Minagawa, Alexander V. Ruban Tags: Bioenergetics Source Type: research
Polymerase {gamma} efficiently replicates through many natural template barriers but stalls at the HSP1 quadruplex [Enzymology]
Faithful replication of the mitochondrial genome is carried out by a set of key nuclear-encoded proteins. DNA polymerase γ is a core component of the mtDNA replisome and the only replicative DNA polymerase localized to mitochondria. The asynchronous mechanism of mtDNA replication predicts that the replication machinery encounters dsDNA and unique physical barriers such as structured genes, G-quadruplexes, and other obstacles. In vitro experiments here provide evidence that the polymerase γ heterotrimer is well-adapted to efficiently synthesize DNA, despite the presence of many naturally occurring roadblocks. However, we ...
Source: Journal of Biological Chemistry - December 18, 2020 Category: Chemistry Authors: Eric D. Sullivan, Matthew J. Longley, William C. Copeland Tags: DNA and Chromosomes Source Type: research
Mouse Ifit1b is a cap1-RNA-binding protein that inhibits mouse coronavirus translation and is regulated by complexing with Ifit1c [RNA]
Knockout mouse models have been extensively used to study the antiviral activity of IFIT (interferon-induced protein with tetratricopeptide repeats). Human IFIT1 binds to cap0 (m7GpppN) RNA, which lacks methylation on the first and second cap-proximal nucleotides (cap1, m7GpppNm, and cap2, m7GpppNmNm, respectively). These modifications are signatures of “self” in higher eukaryotes, whereas unmodified cap0-RNA is recognized as foreign and, therefore, potentially harmful to the host cell. IFIT1 inhibits translation at the initiation stage by competing with the cap-binding initiation factor complex, eIF4F, restricting inf...
Source: Journal of Biological Chemistry - December 18, 2020 Category: Chemistry Authors: Harriet V. Mears, Trevor R. Sweeney Tags: Immunology Source Type: research
The C-terminal region of the plasmid partitioning protein TubY is a tetramer that can bind membranes and DNA [Protein Structure and Folding]
This study determined the crystal structure of the C-terminal domain of TubY from the Bacillus cereus pXO1-like plasmid and showed that it forms a tetrameric parallel four-helix bundle that differs from the typical MerR family proteins with a dimeric anti-parallel coiled-coil. Biochemical analyses revealed that the C-terminal tail with the conserved lysine cluster helps TubY to stably associate with the TubR-centromere complex as well as to nonspecifically bind DNA. Furthermore, this C-terminal tail forms an amphipathic helix in the presence of lipids but must oligomerize to localize the protein to the membrane in vivo. Ta...
Source: Journal of Biological Chemistry - December 18, 2020 Category: Chemistry Authors: Ikuko Hayashi Tags: Protein Structure and Folding Source Type: research
A structural and kinetic survey of GH5_4 endoglucanases reveals determinants of broad substrate specificity and opportunities for biomass hydrolysis [Protein Structure and Folding]
Broad-specificity glycoside hydrolases (GHs) contribute to plant biomass hydrolysis by degrading a diverse range of polysaccharides, making them useful catalysts for renewable energy and biocommodity production. Discovery of new GHs with improved kinetic parameters or more tolerant substrate-binding sites could increase the efficiency of renewable bioenergy production even further. GH5 has over 50 subfamilies exhibiting selectivities for reaction with β-(1,4)–linked oligo- and polysaccharides. Among these, subfamily 4 (GH5_4) contains numerous broad-selectivity endoglucanases that hydrolyze cellulose, xyloglucan, and mi...
Source: Journal of Biological Chemistry - December 18, 2020 Category: Chemistry Authors: Evan M. Glasgow, Elias I. Kemna, Craig A. Bingman, Nicole Ing, Kai Deng, Christopher M. Bianchetti, Taichi E. Takasuka, Trent R. Northen, Brian G. Fox Tags: Enzymology Source Type: research
ARID4B is critical for mouse embryonic stem cell differentiation towards mesoderm and endoderm, linking epigenetics to pluripotency exit [Developmental Biology]
Distinct cell types emerge from embryonic stem cells through a precise and coordinated execution of gene expression programs during lineage commitment. This is established by the action of lineage specific transcription factors along with chromatin complexes. Numerous studies have focused on epigenetic factors that affect embryonic stem cells (ESC) self-renewal and pluripotency. However, the contribution of chromatin to lineage decisions at the exit from pluripotency has not been as extensively studied. Using a pooled epigenetic shRNA screen strategy, we identified chromatin-related factors critical for differentiation tow...
Source: Journal of Biological Chemistry - December 18, 2020 Category: Chemistry Authors: Nihal Terzi Cizmecioglu, Jialiang Huang, Ezgi G. Keskin, Xiaofeng Wang, Idil Esen, Fei Chen, Stuart H. Orkin Tags: Gene Regulation Source Type: research
Snapshots during the catalytic cycle of a histidine acid phytase reveal an induced-fit structural mechanism [Protein Structure and Folding]
Highly engineered phytases, which sequentially hydrolyze the hexakisphosphate ester of inositol known as phytic acid, are routinely added to the feeds of monogastric animals to improve phosphate bioavailability. New phytases are sought as starting points to further optimize the rate and extent of dephosphorylation of phytate in the animal digestive tract. Multiple inositol polyphosphate phosphatases (MINPPs) are clade 2 histidine phosphatases (HP2P) able to carry out the stepwise hydrolysis of phytate. MINPPs are not restricted by a strong positional specificity making them attractive targets for development as feed enzyme...
Source: Journal of Biological Chemistry - December 18, 2020 Category: Chemistry Authors: Isabella M. Acquistapace, Monika A. Zi{cedilla}etek, Arthur W. H. Li, Melissa Salmon, Imke Kuhn, Mike R. Bedford, Charles A. Brearley, Andrew M. Hemmings Tags: Enzymology Source Type: research
Hdac3 regulates bone modeling by suppressing osteoclast responsiveness to RANKL [Signal Transduction]
In this study we conditionally deleted Hdac3 within Ctsk-expressing cells and examined the effects on bone modeling and osteoclast differentiation in mice. Hdac3 deficiency reduced femur and tibia periosteal circumference and increased cortical periosteal osteoclast number. Trabecular bone was likewise reduced and was accompanied by increased osteoclast number per trabecular bone surface. We previously showed that Hdac3 deacetylates the p65 subunit of the NF-κB transcriptional complex to decrease DNA-binding and transcriptional activity. Hdac3-deficient osteoclasts demonstrate increased K310 NF-κB acetylation and NF-κB ...
Source: Journal of Biological Chemistry - December 18, 2020 Category: Chemistry Authors: David H. H. Molstad, Anna M. Mattson, Dana L. Begun, Jennifer J. Westendorf, Elizabeth W. Bradley Tags: Molecular Bases of Disease Source Type: research
Mapping the transition state for a binding reaction between ancient intrinsically disordered proteins [Molecular Biophysics]
Intrinsically disordered protein domains often have multiple binding partners. It is plausible that the strength of pairing with specific partners evolves from an initial low affinity to a higher affinity. However, little is known about the molecular changes in the binding mechanism that would facilitate such a transition. We previously showed that the interaction between two intrinsically disordered domains, NCBD and CID, likely emerged in an ancestral deuterostome organism as a low-affinity interaction that subsequently evolved into a higher-affinity interaction before the radiation of modern vertebrate groups. Here we m...
Source: Journal of Biological Chemistry - December 18, 2020 Category: Chemistry Authors: Elin Karlsson, Cristina Paissoni, Amanda M. Erkelens, Zeinab A. Tehranizadeh, Frieda A. Sorgenfrei, Eva Andersson, Weihua Ye, Carlo Camilloni, Per Jemth Tags: Protein Structure and Folding Source Type: research
Mycobacterium tuberculosis infection up-regulates MFN2 expression to promote NLRP3 inflammasome formation [Cell Biology]
Tuberculosis (TB), caused by the infection of Mycobacterium tuberculosis (MTB), is one of the leading causes of death worldwide, especially in children. However, the mechanisms by which MTB infects its cellular host, activates an immune response, and triggers inflammation remain unknown. Mitochondria play important roles in the initiation and activation of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) inflammasome, where mitochondria-associated endoplasmic reticulum membranes (MAMs) may serve as the platform for inflammasome assembly and activation. Additionally, mitofusin 2 (MFN...
Source: Journal of Biological Chemistry - December 18, 2020 Category: Chemistry Authors: Fang Xu, Hui Qi, Jieqiong Li, Lin Sun, Juanjuan Gong, Yuanying Chen, Adong Shen, Wei Li Tags: Microbiology Source Type: research
