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Nuclear ribonucleoprotein RALY targets virus nucleocapsid protein and induces autophagy to restrict porcine epidemic diarrhea virus replication J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-24 Wenzhen Qin, Ning Kong, Yu Zhang, Sujie Dong, Huanjie Zhai, Xueying Zhai, Xinyu Yang, Chenqian Ye, Manqing Ye, Changlong Liu, Lingxue Yu, Hao Zheng, Hai Yu, Wen Zhang, Guangzhi Tong, Daoliang Lan, Wu Tong, Tongling Shan
Porcine epidemic diarrhea virus (PEDV) causes diarrhea and dehydration in pigs and leads to great economic losses in the commercial swine industry. However, the underlying molecular mechanisms of host response to viral infection remain unclear. In the present study, we investigated a novel mechanism by which RALY, a member of the heterogeneous nuclear ribonucleoprotein family, significantly promotes
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Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-24 Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. Poole, Sharon L. Campbell
The recent development of mutant-selective inhibitors for the oncogenic KRASG12C allele has generated considerable excitement. These inhibitors covalently engage the mutant C12 thiol located within the phosphoryl binding loop of RAS, locking the KRASG12C protein in an inactive state. While clinical trials of these inhibitors have been promising, mechanistic questions regarding the reactivity of this
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Casein kinase 1δ/ε phosphorylates fused in sarcoma (FUS) and ameliorates FUS-mediated neurodegeneration J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-24 Yuya Kishino, Koji Matsukawa, Taisei Matsumoto, Ryota Miyazaki, Tomoko Wakabayashi, Takashi Nonaka, Fuyuki Kametani, Masato Hasegawa, Tadafumi Hashimoto, Takeshi Iwatsubo
Aberrant cytoplasmic accumulation of an RNA-binding protein, fused in sarcoma (FUS), characterizes the neuropathology of subtypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, although the effects of post-translational modifications of FUS, especially phosphorylation, on its neurotoxicity have not been fully characterized. Here we show that casein kinase 1δ phosphorylates
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Ceramide levels in blood plasma correlate with major depressive disorder severity and its neutralization abrogates depressive behavior in mice J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-24 Fabian Schumacher, Michael J. Edwards, Christiane Mühle, Alexander Carpinteiro, Greg Wilson, Barbara Wilker, Matthias Soddemann, Simone Keitsch, Norbert Scherbaum, Bernhard W. Müller, Undine E. Lang, Christoph Linnemann, Burkhard Kleuser, Christian P. Müller, Johannes Kornhuber, Erich Gulbins
Major depressive disorder (MDD) is a severe disease of unknown pathogenesis that will affect ∼10% of people during their lifetime. Therapy for MDD requires prolonged treatment and often fails, predicating a need for novel treatment strategies. Here, we report increased ceramide levels in the blood plasma of MDD patients and in murine stress-induced models of MDD. These blood plasma ceramide levels
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A new deep learning technique reveals the exclusive functional contributions of individual cancer mutations J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-24 Prashant Gupta, Aashi Jindal, Gaurav Ahuja, Jayadeva, Debarka Sengupta
Cancers are caused by genomic alterations that may be inherited, induced by environmental carcinogens, or caused due to random replication errors. Post-induction of carcinogenicity, mutations further propagate and drastically alter the cancer genomes. Although a subset of driver mutations has been identified and characterized to date, most cancer-related somatic mutations are indistinguishable from
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Phosphorylation on Y342 Syk is important for both ITAM and hemITAM signaling in platelets J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-24 John C. Kostyak, Benjamin Mauri, Carol Dangelmaier, Hymavathi Reddy Vari, Akruti Patel, Monica Wright, Haritha Reddy, Alexander Y. Tsygankov, Satya P. Kunapuli
Immune cells express receptors bearing an Immune tyrosine activation motif (ITAM) containing two YXXL motifs or hemITAMs containing only one YXXL motif. Phosphorylation of the ITAM/hemITAM is mediated by Src family kinases allowing for the binding and activation of Spleen tyrosine kinase (Syk). It is believed that Syk must be phosphorylated on tyrosine residues for activation, and Tyr342, а conserved
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A single amino acid residue tunes the stability of the fully reduced flavin cofactor and photorepair activity in photolyases J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-24 Bin Wen, Lei Xu, Yawei Tang, Zhen Jiang, Mengting Ge, Li Liu, Guoping Zhu
The ultraviolet-induced DNA lesions, cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4 photoproducts), can be directly photorepaired by CPD photolyases and 6-4 photolyases, respectively. The fully reduced flavin (hydroquinone, HQ) cofactor is required for the catalysis of both types of these photolyases. On the other hand, flavin cofactor in the semi-reduced state
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DEAD Box 1 (DDX1) protein binds to and protects cytoplasmic stress response mRNAs in cells exposed to oxidative stress J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-23 Lei Li, Mansi Garg, Yixiong Wang, Weiwei Wang, Roseline Godbout
The Integrated Stress Response (ISR) is a network of highly-orchestrated pathways activated when cells are exposed to various types of environmental stressors. While global repression of translation is a well-recognized hallmark of the ISR, less is known about the regulation of mRNA stability during stress. DEAD box proteins are a family of RNA unwinding/remodeling enzymes involved in every aspect
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Identification of the riboflavin-cofactor binding site in the Vibrio cholerae ion-pumping NQR complex: A novel structural motif in redox enzymes J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-23 Karina Tuz, Ming Yuan, Yuyao Hu, Tien T.T. Do, Soohaeng Yoo Willow, Joseph A. DePaolo-Boisvert, James R. Fuller, David D.L. Minh, Oscar Juárez
The ion-pumping NQR complex is an essential respiratory enzyme in the physiology of many pathogenic bacteria. This enzyme transfers electrons from NADH to ubiquinone through several cofactors, including riboflavin (vitamin B2). NQR is the only enzyme reported that is able to use riboflavin as a cofactor. Moreover, the riboflavin molecule is found as a stable neutral semiquinone radical. The otherwise
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Selenoprotein TXNRD3 supports male fertility via the redox regulation of spermatogenesis J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-23 Qianhui Dou, Anton A. Turanov, Marco Mariotti, Jae Yeon Hwang, Huafeng Wang, Sang-Goo Lee, Joao A. Paulo, Sun Hee Yim, Stephen P. Gygi, Jean-Ju Chung, Vadim N. Gladyshev
Thioredoxin/glutathione reductase (TGR, TXNRD3) is a selenoprotein composed of thioredoxin reductase and glutaredoxin domains. This NADPH-dependent thiol oxidoreductase evolved through gene duplication within the Txnrd family, is expressed in the testes, and can reduce both thioredoxin and glutathione in vitro; however, the function of this enzyme remains unknown. To characterize the function of TXNRD3
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Characterizing unexpected interactions of a glutamine transporter inhibitor with members of the SLC1A transporter family J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-23 Natasha Freidman, Chelsea Briot, Renae Ryan
The Solute Carrier 1A (SLC1A) family comprises a group of membrane proteins that act as dual-function amino acid transporters and chloride channels and includes the alanine serine cysteine transporters (ASCTs) as well as the excitatory amino acid transporters (EAATs). ASCT2 is regarded as a promising target for cancer therapy, as it can transport glutamine and other neutral amino acids into cells and
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Polyunsaturated fatty acids promote the rapid fusion of lipid droplets in Caenorhabditis elegans J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-23 Yanli Wang, Chunxia Li, Jingjing Zhang, Xiumei Xu, Lin Fu, Jie Xu, Hong Zhu, Ying Hu, Chengbin Li, Mengjie Wang, Yingjie Wu, Xiaoju Zou, Bin Liang
Lipid droplets (LDs) are intracellular organelles that dynamically regulate lipids and energy homeostasis in the cell. LDs can grow through either local lipid synthesis or LDs fusion. However, how lipids involving in LD fusion for LD growth is largely unknown. Here we show that genetic mutation of acox-3 (acyl-CoA oxidase), maoc-1 (enoyl-CoA hydratase), dhs-28 (3-hydroxylacyl-CoA dehydrogenase), and
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Transcriptional profiling reveals roles of intercellular Fgf9 signaling in astrocyte maturation and synaptic refinement during brainstem development J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-23 Ashley N. Brandebura, Douglas R. Kolson, Emily M. Amick, Jad Ramadan, Matthew C. Kersting, Robert H. Nichol, Paul S. Holcomb, Peter H. Mathers, Peter Stoilov, George A. Spirou
Neural tissue maturation is a coordinated process under tight transcriptional control. We previously analyzed the kinetics of gene expression in the medial nucleus of the trapezoid body (MNTB) in the brainstem during the critical postnatal phase of its development. While this work revealed timed execution of transcriptional programs, it was blind to the specific cells where gene expression changes
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Structural biology of ex vivo mammalian prions J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-23 Efrosini Artikis, Allison Kraus, Byron Caughey
The structures of prion protein (PrP)-based mammalian prions have long been elusive. However, cryo-electron microscopy has begun to reveal the near-atomic resolution structures of fully infectious ex vivo mammalian prion fibrils as well as relatively innocuous synthetic PrP amyloids. Comparisons of these various types of PrP fibrils are now providing initial clues to structural features that correlate
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Clathrin adaptor AP-1-mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments. J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-23 Yunan C. Januário, Jessica Eden, Luan S. de Oliveira, Raffaella De Pace, Lucas A. Tavares, Mara E. da Silva-Januário, Vinícius B. Apolloni, Elise L. Wilby, Randolf Altmeyer, Patricia V. Burgos, Sonia A.L. Corrêa, David C. Gershlick, Luis L.P. daSilva
One of the hallmarks of Alzheimer’s disease (AD) is the accumulation of toxic amyloid-β (Aβ) peptides in extracellular plaques. The direct precursor of Aβ is the carboxyl-terminal fragment (CTFβ or C99) of the amyloid precursor protein (APP). C99 is detected at elevated levels in AD brains and its intracellular accumulation has been linked to early neurotoxicity independently of Aβ. Despite this, the
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RNA editing enzyme ADAR1 controls miR-381-3p-mediated expression of multidrug resistance protein MRP4 via regulation of circRNA in human renal cells J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-23 Yuji Omata, Maseri Okawa, Mai Haraguchi, Akito Tsuruta, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo
Multidrug resistance-associated protein 4 (MRP4), a member of the C subfamily of ATP-binding cassette transporters, is highly expressed in the kidneys of mammals and is responsible for renal elimination of numerous drugs. Adenosine deaminase acting on RNA 1 (ADAR1) has been reported to regulate gene expression by catalyzing adenosine-to-inosine (A-to-I) RNA editing reactions; however, potential roles
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PKGIα is activated by metal-dependent oxidation in vitro but not in intact cells J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-22 Sahar Aminzai, Tingfei Hu, Renate B. Pilz, Darren E. Casteel
Type I cGMP-dependent protein kinases (PKGIs) are important components of various signaling pathways, and are canonically activated by nitric oxide- and natriuretic peptide-induced cGMP generation. However, some reports have shown that PKGIα can also be activated in vitro by oxidizing agents. Using in vitro kinase assays, here we found that purified PKGIα stored in phosphate-buffered saline with Flag
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Impaired Mitophagy in Sanfilippo A mice Causes Hypertriglyceridemia and Brown Adipose Tissue Activation J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-22 Miguel Tillo, William C. Lamanna, Chrissa A. Dwyer, Daniel R. Sandoval, Ariane R. Pessentheiner, Norah Al-Azzam, Stéphane Sarrazin, Jon C. Gonzales, Shih-Hsin Kan, Alexander Y. Andreyev, Nicholas Schultheis, Bryan E. Thacker, Charles A. Glass, Patricia I. Dickson, Raymond Y. Wang, Scott B. Selleck, Jeffrey D. Esko, Philip L.S.M. Gordts
Lysosomal storage diseases result in various developmental and physiological complications, including cachexia. To study the causes for the negative energy balance associated with cachexia, we assessed the impact of sulfamidase deficiency and heparan sulfate storage on energy homeostasis and metabolism in a mouse model of Type IIIa mucopolysaccharidosis (MPS IIIa, Sanfilippo A syndrome). At 12 weeks
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Identification and functional characterization of mRNAs that exhibit stop codon readthrough in Arabidopsis thaliana J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-22 Sarthak Sahoo, Divyoj Singh, Anumeha Singh, Madhuparna Pandit, Kirtana Vasu, Saubhik Som, Naga Jyothi Pullagurla, Debabrata Laha, Sandeep M. Eswarappa
Stop codon readthrough (SCR) is the process of continuation of translation beyond the stop codon, generating protein isoforms with C-terminal extensions. SCR has been observed in viruses, fungi, and multicellular organisms, including mammals. However, SCR is largely unexplored in plants. In this study, we have analyzed ribosome profiling datasets to identify mRNAs that exhibit SCR in Arabidopsis thaliana
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Subcellular dynamics and functional activity of the cleaved intracellular domain of the Na+ channel β1 subunit J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-22 Alexander S. Haworth, Samantha L. Hodges, Alina L. Capatina, Lori L. Isom, Christoph G. Baumann, William J. Brackenbury
The voltage-gated Na+ channel β1 subunit, encoded by SCN1B, regulates cell surface expression and gating of α subunits and participates in cell adhesion. β1 is cleaved by α/β and γ-secretases, releasing an extracellular domain and intracellular domain (ICD), respectively. Abnormal SCN1B expression/function is linked to pathologies including epilepsy, cardiac arrhythmia, and cancer. In this study, we
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Seed-competent tau monomer initiates pathology in a tauopathy mouse model. J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-22 Hilda Mirbaha, Dailu Chen, Vishruth Mullapudi, Sandi Jo Terpack, Charles L. White, Lukasz A. Joachimiak, Marc I. Diamond
Tau aggregation into ordered assemblies causes neurodegenerative tauopathies. We previously reported that tau monomer exists in either inert (Mi) or seed-competent (Ms) conformational ensembles, and that Ms encodes strains, which are unique, self-replicating, biologically active assemblies. It is unknown if disease begins with Ms formation followed by fibril assembly, or if Ms derives from fibrils
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An acyl-adenylate mimic reveals the structural basis for substrate recognition by the iterative siderophore synthetase DesD J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-21 Jinping Yang, Victoria S. Banas, Ketan D. Patel, Gerry S.M. Rivera, Lisa S. Mydy, Andrew M. Gulick, Timothy A. Wencewicz
Siderophores are conditionally essential metabolites used by microbes for environmental iron sequestration. Most Streptomyces strains produce hydroxamate-based desferrioxamine (DFO) siderophores composed of repeating units of N1-hydroxy-cadaverine (or N1-hydroxy-putrescine) and succinate. The DFO biosynthetic operon, desABCD, is highly conserved in Streptomyces; however, expression of desABCD alone
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Recent insights into non-canonical 5′ capping and decapping of RNA J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-21 Selom K. Doamekpor, Sunny Sharma, Megerditch Kiledjian, Liang Tong
The 5′ N7-methylguanosine cap is a critical modification for mRNAs and many other RNAs in eukaryotic cells. Recent studies have uncovered an RNA 5′ capping quality surveillance mechanism, with DXO/Rai1 decapping enzymes removing incomplete caps and enabling the degradation of the RNAs, in a process we also refer to as ‘no-cap decay’. It has also been discovered recently that RNAs in eukaryotes, bacteria
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Insights into the structural dynamics and helicase-catalyzed unfolding of plant RNA G-quadruplexes J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-20 Liu Wang, Ya-Peng Xu, Di Bai, Song-Wang Shan, Jie Xie, Yan Li, Wen-Qiang Wu
RNA G-quadruplexes (rG4s) are non-canonical RNA secondary structures formed by guanine (G)-rich sequences. These complexes play important regulatory roles in both animals and plants through their structural dynamics, and are closely related to human diseases and plant growth, development, and adaption. Thus, studying the structural dynamics of rG4s is fundamentally important; however, their folding
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Copper inhibits protein maturation in the secretory pathway by targeting the Sec61 translocon in Saccharomyces cerevisiae J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-20 Nitu Saha, Raghuvir Singh Tomar
In Saccharomyces cerevisiae, proteins destined for secretion utilize the post-translational translocon machinery to gain entry into the endoplasmic reticulum (ER). These proteins then mature by undergoing a number of post-translational modifications in different compartments of the secretory pathway. While these modifications have been well established for many proteins, to date only a few studies
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Withdrawal: The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-20 Jianhua Wang, Yusuke Shiozawa, Jincheng Wang, Yu Wang, Younghun Jung, Kenneth J. Pienta, Rohit Mehra, Robert Loberg, Russell S. Taichman
Abstract not available
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Self-activating G protein α subunits engage seven-transmembrane Regulator of G protein Signaling (RGS) proteins and a Rho guanine nucleotide exchange factor effector in the amoeba Naegleria fowleri J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-20 Dustin E. Bosch, William R. Jeck, David P. Siderovski
The free-living amoeba Naegleria fowleri is a causative agent of primary amoebic meningoencephalitis and is highly resistant to current therapies, resulting in mortality rates >97%. As many therapeutics target G protein-centered signal transduction pathways, further understanding the functional significance of G protein signaling within N. fowleri should aid future drug discovery against this pathogen
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Structural insights into the function-modulating effects of nanobody binding to the integrin receptor αMβ2 J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-20 Rasmus K. Jensen, Henrik Pedersen, Josefine Lorentzen, Nick Stub Laursen, Thomas Vorup-Jensen, Gregers Rom Andersen
The integrin receptor αMβ2 mediates phagocytosis of complement-opsonized objects, adhesion to the extracellular matrix, and trans-endothelial migration of leukocytes. However, the mechanistic aspects of αMβ2 signaling upon ligand binding are unclear. Here we present the first atomic structure of the human αMβ2 headpiece fragment in complex with the nanobody hCD11bNb1 at a resolution of 3.2 Å. We show
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Nudix hydrolase 18 catalyzes the hydrolysis of active triphosphate metabolites of the antivirals Remdesivir, Ribavirin and Molnupiravir J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-19 Ann-Sofie Jemth, Emma Rose Scaletti, Evert Homan, Pål Stenmark, Thomas Helleday, Maurice Michel
Remdesivir and Molnupiravir have gained considerable interest due to their demonstrated activity against SARS-CoV-2. These antivirals are converted intracellularly to their active triphosphate forms Remdesivir-TP and Molnupiravir-TP. Cellular hydrolysis of these active metabolites would consequently decrease the efficiency of these drugs; however, whether endogenous enzymes that can catalyze this hydrolysis
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Elucidation of binding preferences of YEATS domains to site-specific acetylated nucleosome core particles J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-19 Masaki Kikuchi, Satoshi Morita, Mie Goto, Masatoshi Wakamori, Kazushige Katsura, Kazuharu Hanada, Mikako Shirouzu, Takashi Umehara
Acetylated lysine residues (Kac) in histones are recognized by epigenetic reader proteins, such as Yaf9, ENL, AF9, Taf14, and Sas5 (YEATS) domain-containing proteins. Human YEATS domains bind to the acetylated N-terminal tail of histone H3; however, their Kac-binding preferences at the level of the nucleosome are unknown. Through genetic code reprogramming, here we established a nucleosome core particle
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A transthyretin monomer intermediate undergoes local unfolding and transient interaction with oligomers in a kinetically concerted aggregation pathway J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-18 Xun Sun, James A. Ferguson, H. Jane Dyson, Peter E. Wright
Transthyretin (TTR) amyloidosis is associated with tissue deposition of TTR aggregates. TTR aggregation is initiated by dissociation of the native tetramer to form a monomeric intermediate, which locally unfolds and assembles into soluble oligomers and higher-order aggregates. However, a detailed mechanistic understanding requires kinetic and structural characterization of the low-population intermediates
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Identification of the amino acid residues involved in the species-dependent differences in the pyridoxine transport function of SLC19A3 J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-17 Kohei Miyake, Tomoya Yasujima, Syunsuke Takahashi, Takahiro Yamashiro, Hiroaki Yuasa
Recent studies have shown that human solute carrier SLC19A3 (hSLC19A3) can transport pyridoxine (vitamin B6) in addition to thiamine (vitamin B1), its originally identified substrate, whereas rat and mouse orthologs of hSLC19A3 can transport thiamine but not pyridoxine. This finding implies that some amino acid residues required for pyridoxine transport, but not for thiamine transport, are specific
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A biosensor of protein foldedness identifies increased “holdase” activity of chaperones in the nucleus following increased cytosolic protein aggregation J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-17 Candice B. Raeburn, Angelique R. Ormsby, Dezerae Cox, Chloe A. Gerak, Christian Makhoul, Nagaraj S. Moily, Simon Ebbinghaus, Alex Dickson, Gawain McColl, Danny M. Hatters
Chaperones and other quality control machinery guard proteins from inappropriate aggregation, which is a hallmark of neurodegenerative diseases. However, how the systems that regulate the ‘foldedness’ of the proteome remain buffered under stress conditions and in different cellular compartments remains incompletely understood. In this study, we applied a FRET-based strategy to explore how well quality
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Mapping interactions between the CRAC activation domain and CC1 that regulate the activity of the ER Ca2+ sensor STIM1 J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-17 Nisha Shrestha, Ann Hye-Ryong Shim, Mohammad Mehdi Maneshi, Priscilla See-Wai Yeung, Megumi Yamashita, Murali Prakriya
Stromal interaction molecule 1 (STIM1) is a widely expressed protein that functions as the endoplasmic reticulum (ER) Ca2+ sensor and activator of Orai1 channels. In resting cells with replete Ca2+ stores, an inhibitory clamp formed by the coiled-coil 1 (CC1) domain interacting with the CRAC-activation domain (CAD) of STIM1 helps keep STIM1 in a quiescent state. Following depletion of ER Ca2+ stores
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Expression of a novel mycobacterial phosphodiesterase successfully lowers cAMP levels resulting in reduced tolerance to cell wall-targeting antimicrobials J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-17 Michael Thomson, Yi Liu, Kanokkan Nunta, Ashleigh Cheyne, Nadia Fernandes, Richard Williams, Acely Garza-Garcia, Gerald Larrouy-Maumus
Antimicrobial tolerance, the ability to survive exposure to antimicrobials via transient nonspecific means, promotes the development of antimicrobial resistance (AMR). The study of the molecular mechanisms that result in antimicrobial tolerance is therefore essential for the understanding of AMR. In gram-negative bacteria, the second messenger molecule 3’,5’-cyclic adenosine monophosphate (cAMP) has
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Identification of a distal enhancer that determines the expression pattern of acute phase marker C-reactive protein J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-17 Ming-Yu Wang, Chun-Miao Zhang, Hai-Hong Zhou, Zhong-Bo Ge, Chen-Chen Su, Zi-Hao Lou, Xin-Yun Zhang, Tao-Tao Xu, Si-Yi Li, Li Zhu, Ya-Li Zhou, Yi Wu, Shang-Rong Ji
C-reactive protein (CRP) is a major acute phase protein and inflammatory marker, the expression of which is largely liver-specific and highly inducible. Enhancers are regulatory elements critical for the precise activation of gene expression, yet the contributions of enhancers to the expression pattern of CRP have not been well defined. Here we identify a constitutively active enhancer (E1) located
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Phosphatidic acid species 34:1 mediates expression of the myo-inositol 3-phosphate synthase gene INO1 for lipid synthesis in yeast J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-16 Maria Laura Gaspar, Manuel A. Aregullin, Yu-Fang Chang, Stephen A. Jesch, Susan A. Henry
Depletion of exogenous inositol in yeast results in rising levels of phosphatidic acid (PA) and is correlated with increased expression of genes containing the inositol-dependent upstream activating sequence (UASINO) promoter element. INO1, encoding myo-inositol 3-phosphate synthase, is the most highly regulated of the UASINO-containing genes, but its mechanism of regulation is not clear. In the current
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Structural insights into the role of the WW2 domain on tandem WW/PPxY-motif interactions of oxidoreductase WWOX J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-16 Shahar Rotem-Bamberger, Jamal Fahoum, Keren Keinan-Adamsky, Tomer Tsaban, Orly Avraham, Deborah E. Shalev, Jordan H. Chill, Ora Schueler-Furman
Class I WW domains are present in many proteins of various functions and mediate protein interactions by binding to short linear PPxY motifs. Tandem WW domains often bind peptides with multiple PPxY motifs, but the interplay of WW/peptide interactions is not always intuitive. The WW domain-containing oxidoreductase (WWOX) harbors two WW domains: an unstable WW1 capable of PPxY binding, and stable WW2
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A Human IgE bispecific antibody shows potent cytotoxic capacity mediated by monocytes J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-16 Natasa Vukovic, Samer Halabi, Joan Salvador Russo-Cabrera, Bart Blokhuis, Pedro Berraondo, Frank A.M. Redegeld, Dietmar M.W. Zaiss
The generation of bispecific antibodies (bsAbs) targeting two different antigens opens a new level of specificity and, compared to monoclonal antibodies (mAbs), improved clinical efficacy in cancer therapy. Currently, the different strategies for development of bsAbs primarily focus on IgG isotypes. Nevertheless, in comparison to IgG isotypes, IgE has been shown to offer superior tumor control in preclinical
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Astrocyte ethanol exposure reveals persistent and defined calcium response subtypes and associated gene signatures J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-16 Hyun-Bum Kim, Youtao Lu, Seonkyung C. Oh, Jacqueline Morris, Kevin Miyashiro, Junhyong Kim, James Eberwine, Jai-Yoon Sul
Astrocytes play a critical role in brain function, but their contribution during ethanol (EtOH) consumption remains largely understudied. In light of recent findings on the heterogeneity of astrocyte physiology and gene expression, an approach with the ability to identify subtypes and capture this heterogeneity is necessary. Here, we combined measurements of calcium signaling and gene expression to
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The sodium proton exchanger NHE9 regulates phagosome maturation and bactericidal activity in macrophages J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-16 Habiba S. Shamroukh, Nabrah Lone, Muaaz Akhtar, Alhareth Altayib, Shelby Sutliff, Zahraa Kassem, Suvranta K. Tripathy, Kalyan C. Kondapalli
Acidification of phagosomes is essential for the bactericidal activity of macrophages. Targeting machinery that regulates pH within the phagosomes is a prominent strategy employed by various pathogens that have emerged as major threats to public health. Nascent phagosomes acquire the machinery for pH regulation through a graded maturation process involving fusion with endolysosomes. In addition, meticulous
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Activity-based protein profiling reveals active serine proteases that drive malignancy of human ovarian clear cell carcinoma J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-16 Christine Mehner, Alexandra Hockla, Mathew Coban, Benjamin Madden, Rosendo Estrada, Derek C. Radisky, Evette S. Radisky
Ovarian clear cell carcinoma (OCCC) is an understudied poor prognosis subtype of ovarian cancer lacking in effective targeted therapies. Efforts to define molecular drivers of OCCC malignancy may lead to new therapeutic targets and approaches. Among potential targets are secreted proteases, enzymes which in many cancers serve as key drivers of malignant progression. Here we found that inhibitors of
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Structural variations between small alarmone hydrolase dimers support different modes of regulation of the stringent response J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-15 Francesco Bisiak, Adriana Chrenková, Sheng-Da Zhang, Jannik N. Pedersen, Daniel E. Otzen, Yong E. Zhang, Ditlev E. Brodersen
The bacterial stringent response involves wide-ranging metabolic reprogramming aimed at increasing long-term survivability during stress conditions. One of the hallmarks of the stringent response is the production of a set of modified nucleotides, known as alarmones, which affect a multitude of cellular pathways in diverse ways. Production and degradation of these molecules depend on the activity of
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Structural basis for c-di-AMP-dependent regulation of the bacterial stringent response by receptor protein DarB J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-15 Jana L. Heidemann, Piotr Neumann, Larissa Krüger, Dennis Wicke, Liza Vinhoven, Andreas Linden, Achim Dickmanns, Jörg Stülke, Henning Urlaub, Ralf Ficner
The bacterial second messenger c-di-AMP controls essential cellular processes, including potassium and osmolyte homeostasis. This makes synthesizing enzymes and components involved in c-di-AMP signal transduction intriguing as potential targets for drug development. The c-di-AMP receptor protein DarB of Bacillus subtilis is known to bind the Rel protein and trigger the Rel-dependent stringent response
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The PLEKHA7-PDZD11 complex regulates the localization of the calcium pump PMCA and calcium handling in cultured cells J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-15 Sophie Sluysmans, Andrea Salmaso, Florian Rouaud, Isabelle Méan, Marisa Brini, Sandra Citi
The Plasma Membrane Calcium ATPase (PMCA) extrudes calcium from the cytosol to the extracellular space to terminate calcium-dependent signaling. Although the distribution of PMCA is crucial for its function in calcium homeostasis and signaling, the molecular mechanisms that regulate the localization of PMCA isoforms are not well understood. PLEKHA7 is a junctional protein implicated by genetic studies
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Proximity-based labeling reveals DNA damage-induced phosphorylation of fused in sarcoma (FUS) causes distinct changes in the FUS protein interactome J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-14 Michelle A. Johnson, Thomas A. Nuckols, Paola Merino, Pritha Bagchi, Srijita Nandy, Jessica Root, Georgia Taylor, Nicholas T. Seyfried, Thomas Kukar
Accumulation of cytoplasmic inclusions containing fused in sarcoma (FUS), an RNA/DNA binding protein, is a common hallmark of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) neuropathology. We have previously shown that DNA damage can trigger the cytoplasmic accumulation of N-terminally phosphorylated FUS. However, the functional consequences of N-terminal FUS phosphorylation
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Tumor protein D54 binds intracellular nanovesicles via an extended amphipathic region J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-14 Antoine Reynaud, Maud Magdeleine, Amanda Patel, Anne Sophie Gay, Delphine Debayle, Sophie Abelanet, Bruno Antonny
Tumor Protein D54 (TPD54) is an abundant cytosolic protein that belongs to the TPD52 family, a family of four proteins (TPD52, 53, 54 and 55) that are overexpressed in several cancer cells. Even though the functions of these proteins remain elusive, recent investigations indicate that TPD54 binds to very small cytosolic vesicles with a diameter of ca. 30 nm, half the size of classical (e.g. COPI and
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Hypoxia-inducible factor-1α and poly [ADP ribose] polymerase 1 cooperatively regulate Notch3 expression under hypoxia via a non-canonical mechanism J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-14 Hideaki Nakamura, Hiroki Sekine, Hiroyuki Kato, Hisao Masai, Katarina Gradin, Lorenz Poellinger
Upregulation of Notch3 expression has been reported in many cancers and is considered a marker for poor prognosis. Hypoxia is a driving factor of the Notch3 signaling pathway, however, the induction mechanism and role of hypoxia-inducible factor-1α (HIF-1α) in the Notch3 response are still unclear. In this study, we found that HIF-1α and poly [ADP-ribose] polymerase 1 (PARP-1) regulate Notch3 induction
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Proteasome activator 28γ (PA28γ) allosterically activates trypsin-like proteolysis by binding to the α-ring of the 20S proteasome J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-14 Taylor A. Thomas, David M. Smith
Proteasome Activator 28γ (PA28γ/REGγ) is a member of the 11S family of proteasomal regulators that is constitutively expressed in the nucleus and implicated in various diseases, including certain cancers and systemic lupus erythematosus. Despite years of investigation, how PA28γ functions to stimulate proteasomal protein degradation remains unclear. Many alternative hypotheses have been proposed for
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Sub-stoichiometric Hsp104 regulates the genesis and persistence of self-replicable amyloid seeds of Sup35 prion domain J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-14 Sayanta Mahapatra, Anusha Sarbahi, Priyanka Madhu, Hema M. Swasthi, Abhishek Sharma, Priyanka Singh, Samrat Mukhopadhyay
Prion-like self-perpetuating conformational conversion of proteins is involved in both transmissible neurodegenerative diseases in mammals and non-Mendelian inheritance in yeast. The transmissibility of amyloid-like aggregates is dependent on the stoichiometry of chaperones such as heat shock proteins (Hsps), including disaggregases. To provide the mechanistic underpinnings of the formation and persistence
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Identification and functional implications of pseudouridine RNA modification on small non-coding RNAs in the mammalian pathogen Trypanosoma brucei J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-14 K. Shanmugha Rajan, Katerina Adler, Tirza Doniger, Smadar Cohen-Chalamish, Noa Aharon-Hefetz, Saurav Aryal, Yitzhak Pilpel, Christian Tschudi, Ron Unger, Shulamit Michaeli
Trypanosoma brucei, the parasite that causes sleeping sickness, cycles between an insect and a mammalian host. However, the effect of RNA modifications such as pseudouridinylation on its ability to survive in these two different host environments is unclear. Here, two genome-wide approaches were applied for mapping pseudouridinylation sites (Ψs) on small nucleolar RNA (snoRNA), 7SL RNA, vtRNA, and
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Conformational flexibility in carbapenem hydrolysis drives substrate specificity of the class D carbapenemase OXA-24/40 J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-14 Joshua M. Mitchell, Cynthia M. June, Vincent L. Baggett, Beth C. Lowe, James F. Ruble, Robert A. Bonomo, David A. Leonard, Rachel A. Powers
The evolution of multidrug resistance (MDR) in Acinetobacter spp. increases the risk of our best antibiotics losing their efficacy. From a clinical perspective, the carbapenem-hydrolyzing class D β-lactamase (CHDL) subfamily present in Acetinobacter spp. is particularly concerning due to its ability to confer resistance to carbapenems. The kinetic profiles of class D β-lactamases exhibit variability
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Elesclomol elevates cellular and mitochondrial iron levels by delivering copper to the iron import machinery J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-14 Natalie M. Garza, Mohammad Zulkifli, Vishal M. Gohil
Copper (Cu) and iron (Fe) are redox-active metals that serve as cofactors for many essential cellular enzymes. Disruption in the intracellular homeostasis of these metals results in debilitating and frequently fatal human disorders, such as Menkes disease and Friedreich’s ataxia. Recently, we reported that an investigational anticancer drug, elesclomol (ES), can deliver Cu to critical mitochondrial
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Oxidative stress activates transcription of Salmonella pathogenicity island-2 genes in macrophages J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-14 Ju-Sim Kim, Lin Liu, Bennett Davenport, Sashi Kant, Thomas E. Morrison, Andres Vazquez-Torres
The type III secretion system encoded in the Salmonella pathogenicity island-2 (SPI-2) gene cluster facilitates intracellular growth of nontyphoidal Salmonella by interfering with the maturation of Salmonella-containing vacuoles along the degradative pathway. SPI-2 gene products also protect Salmonella against the antimicrobial activity of reactive oxygen species (ROS) synthesized by the phagocyte
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A Naturally Occurring Membrane-Anchored Gαs Variant, XLαs, Activates Phospholipase Cβ4 J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-13 Hoa T.N. Phan, Joseph Loomis, Saji Abraham, Qing He, Murat Bastepe, Alan V. Smrcka
Extra-large stimulatory Gα (XLαs) is a large variant of G protein αs subunit (Gαs) that uses an alternative promoter and thus differs from Gαs at the first exon. XLαs activation by G Protein-Coupled Receptors (GPCRs) mediates cyclic adenose monophosphate (cAMP) generation, similarly to Gαs; however, Gαs and XLαs have been shown to have distinct cellular and physiological functions. For example, previous
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A multi-omics analysis reveals that the lysine deacetylase ABHD14B influences glucose metabolism in mammals J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-11 Abinaya Rajendran, Amarendranath Soory, Neha Khandelwal, Girish Ratnaparkhi, Siddhesh S. Kamat
The sirtuins and histone deacetylases are the best characterized members of the lysine deacetylase (KDAC) enzyme family. Recently, we annotated the “orphan” enzyme ABHD14B (α/β-hydrolase domain containing protein # 14B) as a novel KDAC, showed this enzyme’s ability to transfer an acetyl-group from protein lysine residue(s) to coenzyme-A (CoA) to yield acetyl-CoA, expanding the repertoire of this enzyme
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Combined proteomic and biochemical analyses redefine the consensus sequence requirement for epidermal growth factor-like domain hydroxylation J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-11 Lennart Brewitz, Bruce C. Onisko, Christopher J. Schofield
Epidermal growth factor-like domains (EGFDs) have important functions in cell-cell signaling. Both secreted and cell surface human EGFDs are subject to extensive modifications, including aspartate- and asparagine-residue C3-hydroxylations catalyzed by the 2-oxoglutarate oxygenase aspartate/asparagine-β-hydroxylase (AspH). Although genetic studies show AspH is important in human biology, studies on
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RNA induces unique tau strains and stabilizes Alzheimer’s disease seeds J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-11 Amy N. Zwierzchowski-Zarate, Aydé Mendoza-Oliva, Omar M. Kashmer, Josue E. Collazo-Lopez, Charles L. White, Marc I. Diamond
Tau aggregation underlies neurodegenerative tauopathies, and trans-cellular propagation of tau assemblies of unique structure, i.e. strains, may underlie the diversity of these disorders. Polyanions have been reported to induce tau aggregation in vitro, but the precise trigger to convert tau from an inert to a seed-competent form in disease states is unknown. RNA triggers tau fibril formation in vitro
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Evolutionary Origin and Functional Diversification of Aminotransferases J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-11 Kaan Koper, Sang-Woo Han, Delia Casas Pastor, Yasuo Yoshikuni, Hiroshi A. Maeda
Aminotransferases (ATs) are pyridoxal 5′-phosphate (PLP)-dependent enzymes that catalyze the transamination reactions between amino acid donor and keto acid acceptor substrates. Modern AT enzymes constitute ∼2% of all classified enzymatic activities, play central roles in nitrogen metabolism, and generate multitude of primary and secondary metabolites. ATs likely diverged into four distinct AT classes
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Characterization of a [4Fe-4S]-dependent LarE sulfur insertase that facilitates nickel-pincer nucleotide cofactor biosynthesis in Thermotoga maritima J. Biol. Chem. (IF 5.157) Pub Date : 2022-06-11 Shramana Chatterjee, Kristine F. Parson, Brandon T. Ruotolo, John McCracken, Jian Hu, Robert P. Hausinger
Sulfur-insertion reactions are essential for the biosynthesis of several cellular metabolites, including enzyme cofactors. In Lactobacillus plantarum, a sulfur-containing nickel-pincer nucleotide (NPN) cofactor is used as a coenzyme of lactic acid racemase, LarA. During NPN biosynthesis in L. plantarum, sulfur is transferred to a nicotinic acid-derived substrate by LarE, which sacrifices the sulfur