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Activation of the Snail transcription factor induces Mdm2 gene expression. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-21 Alexander R Mabry,James Gorman,Juan S Delvasto,Andrew R Lavik,Justin H Layer,Lindsey D Mayo
Epithelial-like tumor cells can become metastatic by undergoing molecular and phenotypic reprogramming in a process referred to as epithelial-to-mesenchymal transition (EMT). In response to EMT genes that promote migration and condition the tumor microenvironment to permit intravasation into the bloodstream, dissemination, and extravasation into new organs are induced. While the mutant p53 has been
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Sphingolipids containing very long-chain fatty acids regulate Ypt7 function during the tethering stage of vacuole fusion. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-20 Chi Zhang,Jorge D Calderin,Logan R Hurst,Zeynep D Gokbayrak,Michael R Hrabak,Adam Balutowski,David A Rivera-Kohr,Thomas D D Kazmirchuk,Christopher L Brett,Rutilio A Fratti
Sphingolipids are essential in membrane trafficking and cellular homeostasis. Here, we show that sphingolipids containing very long-chain fatty acids (VLCFAs) promote homotypic vacuolar fusion in Saccharomyces cerevisiae. The elongase Elo3 adds the last two carbons to VLCFAs that are incorporated into sphingolipids. Cells lacking Elo3 have fragmented vacuoles, which is also seen when WT cells are treated
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Oxygen-dependent regulation of F-box proteins in Toxoplasma gondii is mediated by Skp1 glycosylation. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-20 Msano N Mandalasi,Elisabet Gas-Pascual,Carlos Gustavo Baptista,Bowen Deng,Hanke van der Wel,John A W Kruijtzer,Geert-Jan Boons,Ira J Blader,Christopher M West
A dynamic proteome is required for cellular adaption to changing environments including levels of O2, and the SKP1/CULLIN-1/F-box protein/RBX1 (SCF) family of E3 ubiquitin ligases contributes importantly to proteasome-mediated degradation. We examine, in the apicomplexan parasite Toxoplasma gondii, the influence on the interactome of SKP1 by its novel glycan attached to a hydroxyproline generated by
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Structural mechanism of human HCN1 hyperpolarization-activated channel inhibition by ivabradine. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-20 Tong Che,Wei Zhang,Xinyu Cheng,Sijia Lv,Minqing Zhang,Yuting Zhang,Tingting Yang,Weiwei Nan,Shuangyan Wan,Bo Zeng,Jian Li,Bing Xiong,Jin Zhang
The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a crucial role in regulating neuronal excitability. Despite growing evidence supporting the therapeutic potential of HCN1 inhibition in treating neurological disorders, the structural basis of channel inhibition by inhibitor has remained elusive. Here, we present the cryo-electron microscopy structure of human HCN1 channel
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Aberrant overexpression of myosin 1b in glioblastoma promotes angiogenesis via VEGF-myc-myosin 1b-Piezo1 axis. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-20 Weifeng Lv,Fan Yang,Zhengmao Ge,Lele Xin,Lingxue Zhang,Yaohong Zhai,Xian Liu,Qingdong Guo,Xinggang Mao,Peng Luo,Lei Zhang,Xiaofan Jiang,Yanyu Zhang
Glioblastoma (GBM) is the most aggressive intracranial malignancy with poor prognosis. Enhanced angiogenesis is an essential hallmark of GBM, which demonstrates extensive microvascular proliferation and abnormal vasculature. Here, we uncovered the key role of myosin 1b in angiogenesis and vascular abnormality in GBM. Myosin 1b is upregulated in GBM endothelial cells (ECs) compared to the paired non-malignant
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Integrated multi-omics unveil the impact of H-phosphinic analogues of glutamate and α-ketoglutarate on Escherichia coli metabolism. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-20 Fabio Giovannercole,Luís Gafeira Gonçalves,Jean Armengaud,Ana Varela Coelho,Alex Khomutov,Daniela De Biase
Desmethylphosphinothricin (L-Glu-γ-PH) is the H-phosphinic analogue of glutamate with carbon-phosphorus-hydrogen (C-P-H) bonds. In L-Glu-γ-PH the phosphinic group acts as a bioisostere of glutamate γ-carboxyl group allowing the molecule to be a substrate of Escherichia coli glutamate decarboxylase, a pyridoxal 5'-phosphate-dependent α-decarboxylase. In addition, the L-Glu-γ-PH decarboxylation product
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Identification of Cables1 as a critical host factor that promotes ALV-J replication via genome-wide CRISPR/Cas9 gene knockout screening. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-20 Peng Liu,Jinghua Jiang,Yuntong Chen,Fei Gao,Suyan Wang,Mengmeng Yu,Yongzhen Liu,Ru Guo,Li Zhang,Zhuangzhuang Xu,Caiying Wang,Xiaole Qi,Yanping Zhang,Hongyu Cui,Yulu Duan,Sen Wu,Yulong Gao
Avian leukosis virus subgroup J (ALV-J), a member of the genus Alpharetrovirus, possesses a small genome and exploits a vast array of host factors during its replication cycle. To identify host factors required for ALV-J replication and potentially guide the development of key therapeutic targets for ALV-J prevention, we employed a chicken genome-wide CRISPR/Cas9 knockout library to screen host factors
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Characterization of a cytochrome P450 that catalyzes the O-demethylation of lignin-derived benzoates. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-20 Megan E Wolf,Daniel J Hinchen,John E McGeehan,Lindsay D Eltis
Cytochromes P450 (P450s) are a superfamily of heme-containing enzymes possessing a broad range of monooxygenase activities. One such activity is O-demethylation, an essential and rate-determining step in emerging strategies to valorize lignin that employ carbon-carbon bond cleavage. We recently identified PbdA, a P450 from Rhodococcus jostii RHA1, and PbdB, its cognate reductase, which catalyze the
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GDF10 is a negative regulator of vascular calcification. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-20 Khrystyna Platko,Gabriel Gyulay,Paul F Lebeau,Melissa E MacDonald,Edward G Lynn,Jae Hyun Byun,Suleiman A Igdoura,Rachel M Holden,Anna Roubtsova,Nabil G Seidah,Joan C Krepinsky,Richard C Austin
Cardiovascular mortality is particularly high and increasing in patients with chronic kidney disease, with vascular calcification (VC) a major pathophysiologic feature. VC is a highly regulated biological process similar to bone formation involving osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). We have previously demonstrated that loss of T-cell death associated gene 51 (TDAG51)
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Involvement of mitogen- and stress-activated protein kinase (MSK)1 in BMP-6-induced chondrocyte differentiation. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-20 Naoko Nakano,Etsu Tashiro,Takayuki Shimada,Masayasu Ebisawa,Sayaka Kojima,Kaho Ayabe,Yohei Yamamoto,Shingo Maeda,Fumiko Itoh,Susumu Itoh
Bone morphogenetic proteins (BMPs) are involved in several cellular responsive actions, such as development, cell differentiation, and apoptosis, via their specific transmembrane receptors. In particular, BMPs promote the differentiation and maturation of bone and cartilage from mesenchymal stem cells. Based on comprehensive analyses performed with a large number of antibodies, mitogen- and stress-activated
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Nucleolin Malonylation as a Nuclear-Cytosol Signal Exchange Mechanism to Drive Cell Proliferation in Hepatocarcinoma by Enhancing AKT Translation. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-19 Liang Sun,Hanjing Meng,Tao Liu,Qiong Zhao,Mingyi Xia,Zhongjun Zhao,Yuting Qian,Hao Cui,Xuefei Zhong,Keli Chai,Yang Tian,Yang Sun,Bao Zhu,Jiehui Di,Guanghou Shui,Lianjun Zhang,Junnian Zheng,Shutao Guo,Yong Liu
Cancer cells undergo metabolic reprogramming that is intricately linked to malignancy. Protein acylations are especially responsive to metabolic changes, influencing signal transduction pathways and fostering cell proliferation. However, as a novel type of acylations, the involvement of malonylation in cancer remains poorly understood. In this study, we observed a significant reduction in malonyl-CoA
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The ubiquitin-specific protease 21 is critical for cancer cell mitochondrial function and regulates proliferation and migration. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-19 Magdalena Kulma,Bartłomiej Hofman,Małgorzata Szostakowska-Rodzoś,Dorota Dymkowska,Remigiusz Serwa,Katarzyna Piwowar,Agnieszka Belczyk-Ciesielska,Joanna Grochowska,Irina Tuszyńska,Angelika Muchowicz,Katarzyna Drzewicka,Krzysztof Zabłocki,Zbigniew Zasłona
Ubiquitin-Specific Peptidases (USPs) are the main members of deubiquitinases (DUBs) that catalyze removing ubiquitin chains from target proteins, thereby modulating their half-life and function. Enzymatic activity of USP21 regulates protein degradation which is critical for maintaining cell homeostasis. USP21 determines the stability of oncogenic proteins and therefore is implicated in carcinogenesis
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Structure of the endogenous insect acetyl-coA carboxylase carboxyltransferase domain. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-19 Dong Wang,Fan Bu,Ge Yang,Hannah Brenke,Bin Liu
Acetyl-coenzyme A carboxylases (ACCs) are pivotal in fatty acid metabolism, converting acetyl-CoA to malonyl-CoA. While ACCs in humans, plants, and microbes have been extensively studied, insect ACCs, crucial for lipid biosynthesis and physiological processes, remain relatively unexplored. Unlike mammals, which have ACC1 and ACC2 in different tissues, insects possess a single ACC gene, underscoring
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Light-driven Anion-Pumping Rhodopsin with Unique Cytoplasmic Anion-release Mechanism. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-19 Tomohiro Ishizuka,Kano Suzuki,Masae Konno,Keisei Shibata,Yuma Kawasaki,Hidefumi Akiyama,Takeshi Murata,Keiichi Inoue
Microbial rhodopsins are photoreceptive membrane proteins found in microorganisms with an all-trans-retinal chromophore. The function of many microbial rhodopsins is determined by three residues in the third transmembrane helix called motif residues. Here, we report a group of microbial rhodopsins with a novel Thr-Thr-Gly (TTG) motif. The ion-transport assay revealed that they function as light-driven
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Development of a high throughput cytochrome P450-ligand binding assay. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-19 Elyse Frydendall,Emily E Scott
Human cytochrome P450 enzymes are membrane-embedded monooxygenases responsible for xenobiotic metabolism, steroidogenesis, fatty acid metabolism, and vitamin metabolism. Their active sites can accommodate diverse small molecules and understanding these interactions is key to decoding enzymatic functionality and designing drugs. The most common method for characterizing small molecule binding is quantifying
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Microtubule-associated protein, MAP1B, encodes functionally distinct polypeptides. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-19 Tracy C Tan,Yusheng Shen,Lily B Stine,Barbara Mitchell,Kyoko Okada,Richard J McKenney,Kassandra M Ori-McKenney
Microtubule-associated protein, MAP1B, is crucial for neuronal morphogenesis and disruptions in MAP1B function are correlated with neurodevelopmental disorders. MAP1B encodes a single polypeptide that is processed into discrete proteins, a heavy chain (HC) and a light chain (LC); however, it is unclear if these two chains operate individually or as a complex within the cell. In vivo studies have characterized
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Cooperative Folding as a Molecular Switch in an Evolved Antibody Binder. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-19 Malin Jönsson,Ameeq Ul Mushtaq,Tamás Milán Nagy,Emma von Witting,John Löfblom,Kwangho Nam,Magnus Wolf-Watz,Sophia Hober
Designing proteins with tunable activities from easily accessible external cues remains a biotechnological challenge. Here, we set out to create a small antibody-binding domain equipped with a molecular switch inspired by the allosteric response to calcium seen in naturally derived proteins like calmodulin. We have focused on one of the three domains of Protein G that show inherent affinity to antibodies
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Histone methyltransferase KMT2A: Developmental regulation to oncogenic transformation. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-18 Jayme Ogino,Yali Dou
Our current understanding of epigenetic regulation is deeply rooted in the founding contributions of Dr. C. David Allis. In 2002, Allis and colleagues first characterized the lysine methyltransferase activity of the mammalian KMT2A (MLL1), a paradigm shifting discovery that brings epigenetic dysregulation into focus for many human diseases that carry KMT2A mutations. This review will discuss the current
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A novel EZH1/2 dual inhibitor inhibits GCB DLBCL through Cell Cycle Regulation and M2 Tumor-Associated Macrophage Polarization. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-18 Ran An,Zhimeng Zhang,Dongli Zhang,Yuqing Li,Yueling Lin,Hongtao Sun,Fang Xu,Manmei Li,Zhong Liu
The incidence of germinal center B-cell-like type diffuse large B-cell lymphoma (GCB DLBCL) is steadily increasing, with a known hereditary component. Although some molecular mechanisms in GCB DLBCL have been elucidated, understanding remains incomplete, limiting the effectiveness of targeted therapies. In GCB DLBCL patients, abnormally high expression of zeste homologs 2 (EZH2) is noted, and the compensatory
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Differential functional role of Orai1 variants in constitutive Ca2+ entry and calcification in luminal breast cancer cells. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-18 Alejandro Berna-Erro,Jose Javier Lopez,Isaac Jardin,Jose Sanchez-Collado,Gines M Salido,Juan A Rosado
Resting cytosolic Ca2+ concentration is tightly regulated to fine-tune Ca2+-dependent cellular functions. Luminal breast cancer cells exhibit constitutive Ca2+ entry mediated by Orai1 and the secretory pathway Ca2+-ATPase, SPCA2, which result in mammary microcalcifications that constitute a prognostic marker of mammary lesions. Two Orai1 isoforms have been identified, the full-length Orai1α, consisting
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Protein phosphatase PP2Cα S-glutathionylation regulates cell migration. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-18 Dhanushika S K Kukulage,Kusal T G Samarasinghe,Nadee N J Matarage Don,Madhu C Shivamadhu,Kyosuke Shishikura,William Schiff,Faezeh Mashhadi Ramezani,Rayavarapu Padmavathi,Megan L Matthews,Young-Hoon Ahn
Redox signaling is a fundamental mechanism that controls all major biological processes partly via protein cysteine oxidations, including S-glutathionylation. Despite over 2,000 cysteines identified to form S-glutathionylation in databases, the identification of redox cysteines functionally linked to a biological process of interest remains challenging. Here, we demonstrate a strategy combining glutathionylation
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The prodomain of bone morphogenetic protein 2 promotes dimerization and cleavage of BMP6 homodimers and BMP2/6 heterodimers. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-18 Pooja Chauhan,Yongqiang Xue,Hyung-Seok Kim,Allison L Fisher,Jodie L Babitt,Jan L Christian
Bone morphogenetic protein 2 (BMP2) and BMP6 are key regulators of systemic iron homeostasis. All BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the bioactive ligand and inactive prodomain fragments, but nothing is known about how BMP2 or BMP6 homodimeric or heterodimeric precursor proteins are proteolytically activated. Here, we conducted in vitro cleavage
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ADAR promotes USP38 auto-deubiquitylation and stabilization in an RNA editing-independent manner in Esophageal Squamous Cell Carcinoma. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-18 Qingyong Hu,Yahui Chen,Qianru Zhou,Shanshan Deng,Wei Hou,Yong Yi,Chenghua Li,Jiancai Tang
Esophageal cancer is mainly divided into esophageal adenocarcinoma (EADC) and esophageal squamous cell carcinoma (ESCC). China is one of the high-incidence areas of esophageal cancer, of which about 90% are ESCC. The deubiquitinase USP38 has been reported to play significant roles in several biological processes, including inflammatory responses, antiviral infection, cell proliferation, migration,
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Downregulation of the m6A reader YTHDC2 upregulates exosome content in lung adenocarcinoma via inhibiting IFIT and OAS family members. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-18 Zhixin Yin,Lifang Ma,Xiaoting Tian,Qi Sun,Congcong Zhang,Yikun Wang,Yayou Miao,Xiangfei Xue,Yongjie Wang,Jiayi Wang,Xiao Zhang,Xumin Hou
N6-Methyladenosine (m6A) is the most prevalent mRNA modification. Its biological function primarily relies on its "Reader" protein, such as YTHDC2. Previous studies have shown that YTHDC2 downregulation is a pro-carcinogenic phenomenon in lung adenocarcinoma (LUAD). However, further investigation is needed to understand the molecular mechanisms of downstream genes and the associated biological phenomena
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The N-acetylglucosaminyltransferase Radical Fringe contributes to defects in JAG1-dependent turnover and signaling of NOTCH3 CADASIL mutants. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-18 Shodai Suzuki,Taiki Mashiko,Yohei Tsukamoto,Miyu Oya,Yuki Kotani,Saki Okawara,Takemi Matsumoto,Yuki Mizue,Hideyuki Takeuchi,Tetsuya Okajima,Motoyuki Itoh
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic vascular dementia characterized by age-related degeneration of vascular mural cells and accumulation of a NOTCH3 mutant protein. NOTCH3 functions as a signaling receptor, activating downstream gene expression in response to ligands like JAG1 and DLL4, which regulate the development and
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Acetyl-CoA carboxylase Inhibition increases retinal pigment epithelial cell fatty acid flux and restricts apolipoprotein efflux. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-12 Daniel T Hass,Kriti Pandey,Abbi Engel,Noah Horton,Cameron D Haydinger,Brian M Robbings,Rayne R Lim,Martin Sadilek,Qitao Zhang,Gillian A Gulette,Amy Li,Libin Xu,Jason M L Miller,Jennifer R Chao,James B Hurley
Lipid-rich deposits called drusen accumulate under the retinal pigment epithelium (RPE) in the eyes of patients with age-related macular degeneration (AMD) and Sorsby's fundus dystrophy (SFD). Drusen may contribute to photoreceptor and RPE degeneration in these blinding diseases. We hypothesize that stimulating β-oxidation of fatty acids could decrease the availability of lipid with which RPE cells
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Impaired endocytosis and accumulation in early endosomal compartments defines herpes simplex virus–mediated disruption of the nonclassical MHC class I–related molecule MR1 J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-12 Carolyn Samer, Hamish E.G. McWilliam, Brian P. McSharry, James G. Burchfield, Richard J. Stanton, Jamie Rossjohn, Jose A. Villadangos, Allison Abendroth, Barry Slobedman
Presentation of metabolites by the major histocompatibility complex class I–related protein 1 (MR1) molecule to mucosal-associated invariant T cells is impaired during herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections. This is surprising given these viruses do not directly synthesise MR1 ligands. We have previously identified several HSV proteins responsible for rapidly downregulating
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SENP3 mediates the deSUMOylation and degradation of YAP1 to regulate the progression of triple-negative breast cancer. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-11 Xu Chen,Danqing Li,Qi Su,Xing Ling,Yanyan Yang,Yuhang Liu,Xinjie Zhu,Anqi He,Siyu Ding,Runxiao Xu,Zhaoxia Liu,Xiaojun Long,Jinping Zhang,Zhihui Yang,Yitao Qi,Hongmei Wu
Triple-negative breast cancer (TNBC) is a prevalent malignancy in women, casting a formidable shadow on their well-being. Positioned within the nucleolus, SUMO-specific protease 3 (SENP3) assumes a pivotal role in the realms of development and tumorigenesis. However, the participation of SENP3 in TNBC remains a mystery. Here, we elucidate that SENP3 exerts inhibitory effects on migration and invasion
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USP11 deubiquitinates E-cadherin and maintains luminal fate of mammary tumor cells to suppress breast cancer. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-11 Tao Qian,Feng Bai,Shiwen Zhang,Yuping Xu,Yuchan Wang,Shuping Yuan,Xiong Liu,Yaru Du,Bin Peng,Wei-Guo Zhu,Xingzhi Xu,Xin-Hai Pei
Basal-like breast cancer may originate from luminal epithelial or cancerous cells. Inadequately repaired DNA damage impairs luminal differentiation and promotes aberrant luminal to basal trans-differentiation in mammary epithelial cells (MECs). Ubiquitin-specific peptidase 11 (USP11), a deubiquitinase, plays a critical role in DNA damage repair. The role of USP11 in controlling mammary cell differentiation
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Evolutionary and molecular basis of ADP-ribosylation reversal by zinc-dependent macrodomains. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-11 Antonio Ariza,Qiang Liu,Nathan Cowieson,Ivan Ahel,Dmitri V Filippov,Johannes Gregor Matthias Rack
Dynamic ADP-ribosylation signalling is a crucial pathway that controls fundamental cellular processes, in particular, the response to cellular stresses such as DNA damage, reactive oxygen species and infection. In some pathogenic microbes the response to oxidative stress is controlled by a SirTM/zinc-containing macrodomain (Zn-Macro) pair responsible for establishment and removal of the modification
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Three classes of propofol binding sites on GABAA receptors. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-11 Zi-Wei Chen,Satyanarayana M Chintala,John Bracamontes,Yusuke Sugasawa,Spencer R Pierce,Balazs R Varga,Edward H Smith,Christopher J Edge,Nicholas P Franks,Wayland Wl Cheng,Gustav Akk,Alex S Evers
Propofol is a widely used anesthetic and sedative that acts as a positive allosteric modulator (PAM) of gamma-aminobutyric acid type A (GABAA) receptors. Several potential propofol binding sites that may mediate this effect have been identified using propofol-analogue photoaffinity labeling. o-PD labels β-H267, a pore-lining residue, whereas AziPm labels residues β-M286, β-M227 and α-I239 in the two
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LAT1 supports mitotic progression through Golgi unlinking in an amino acid transport activity-independent manner. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-11 Sakura Yanagida,Ryuzaburo Yuki,Youhei Saito,Yuji Nakayama
Amino acid transporters play a vital role in cellular homeostasis by maintaining protein synthesis. L-type amino acid transporter 1 (LAT1/SLC7A5/CD98lc) is a major transporter of large neutral amino acids in cancer cells because of its predominant expression. Although amino acid restriction with various amino acid analog treatments is known to induce mitotic defects, the involvement of amino acid transporters
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New targets and designed inhibitors of ASAP Arf-GAPs derived from structural characterization of the ASAP1/440-kD ankyrin-B interaction. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-10 Yubing Li,Yipeng Zhao,Yaojun He,Fang Liu,Lu Xia,Kai Liu,Mingjie Zhang,Keyu Chen
ASAP1 and its paralog ASAP2 belong to a PI4,5P2-dependent Arf GTPase-activating protein (Arf-GAP) family capable of modulating membrane and cytoskeletal dynamics. ASAPs regulate cell adhesive structures such as invadosomes and focal adhesions during cell attachment and migration. Malfunctioning of ASAP1 has been implicated in the malignant phenotypes of various cancers. Here, we discovered that the
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Modeling protease-sensitive human pancreatic lipase mutations in the mouse ortholog. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-10 Gyula Hoffka,Samara Mhana,Marcell Vas,Vanda Toldi,János András Mótyán,József Tőzsér,András Szabó
Pancreatic lipase (PNLIP) is the major lipolytic enzyme secreted by the pancreas. A recent study identified human PNLIP variants P245A, I265R, F300L, S304F, and F314L in European chronic pancreatitis cohorts. Functional analyses indicated that the variants were normally secreted but exhibited reduced stability when exposed to pancreatic proteases. Proteolysis of the PNLIP variants yielded an intact
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Cortisol affects macrophage polarization by inducing miR-143/145 cluster to reprogram glucose metabolism and by promoting TCA cycle anaplerosis J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-10 Amod Sharma, Kunwar Somesh Vikramdeo, Sarabjeet Kour Sudan, Shashi Anand, Sachin Kumar Deshmukh, Ajay Pratap Singh, Seema Singh
Chronic stress can have adverse consequences on human health by disrupting the hormonal balance in our body. Earlier, we observed elevated levels of cortisol, a primary stress hormone, and some exosomal microRNAs in the serum of patients with breast cancer. Here, we investigated the role of cortisol in microRNA induction and its functional consequences. We found that cortisol induced the expression
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Role of Ammonia Lyases in the Synthesis of the Dithiomethylamine Ligand During [FeFe]-hydrogenase Maturation. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-09 Adrien Pagnier,Batuhan Balci,Eric M Shepard,Hao Yang,Alex Drena,Gemma L Holliday,Brian M Hoffman,William E Broderick,Joan B Broderick
The generation of an active [FeFe]-hydrogenase requires the synthesis of a complex metal center, the H-cluster, by three dedicated maturases: the radical S-adenosyl-l-methionine (SAM) enzymes HydE and HydG, and the GTPase HydF. A key step of [FeFe]-hydrogenase maturation is the synthesis of the dithiomethylamine (DTMA) bridging ligand, a process recently shown to involve the aminomethyl-lipoyl-H-protein
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Murine Nuclear Tyrosyl-tRNA Synthetase Deficiency Leads to Fat Storage Deficiency and Hearing Loss. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-09 Julia A Jones,Jiadong Zhou,Jianjie Dong,Salvador Huitron-Resendiz,Ely Boussaty,Eduardo Chavez,Na Wei,Calin Dan Dumitru,Yosuke Morodomi,Taisuke Kanaji,Allen F Ryan,Rick Friedman,Tong Zhou,Sachiko Kanaji,Matthew Wortham,Simon Schenk,Amanda J Roberts,Xiang-Lei Yang
Aminoacyl-tRNA synthetases (aaRS) are fundamental to the translation machinery with emerging roles in transcriptional regulation. Previous cellular studies have demonstrated tyrosyl-tRNA synthetase (YARS1 or TyrRS) as a stress response protein through its cytosol-nucleus translocation to maintain cellular homeostasis. Here, we established a mouse model with a disrupted TyrRS nuclear localization signal
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Polymyxin B1 in the E. coli inner membrane: a complex story of protein and lipopolysaccharide mediated insertion. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-09 Dhanushka Weerakoon,Jan K Marzinek,Conrado Pedebos,Peter J Bond,Syma Khalid
The rise in multi-drug resistant Gram-negative bacterial infections has led to an increased need for 'last-resort' antibiotics such as polymyxins. However, the emergence of polymyxin-resistant strains threatens to bring about a post-antibiotic era. Thus, there is a need to develop new polymyxin-based antibiotics, but a lack of knowledge of the mechanism of action of polymyxins hinders such efforts
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Probing the nucleobase selectivity of RNA polymerases with dual-coding substrates. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-09 Janne J Mäkinen,Petja Rosenqvist,Pasi Virta,Mikko Metsä-Ketelä,Georgiy A Belogurov
Formycin A (FOR) and Pyrazofurin A (PYR) are nucleoside analogues with antiviral and antitumor properties. They are known to interfere with nucleic acid metabolism, but their direct effect on transcription is less understood. We explored how RNA polymerases (RNAPs) from bacteria, mitochondria, and viruses utilize FOR, PYR, and oxidized purine nucleotides. All tested polymerases incorporated FOR in
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The pro-inflammatory cytokines IL-1β and IL-6 promote upregulation of the ST6GAL1 sialyltransferase in pancreatic cancer cells. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-09 Austin D Silva,Jihye Hwang,Michael P Marciel,Susan L Bellis
The ST6GAL1 sialyltransferase is overexpressed in multiple cancers including pancreatic ductal adenocarcinoma (PDAC). ST6GAL1 adds an α2-6-linked sialic acid to N-glycosylated membrane receptors, which consequently modulates receptor structure and function. While many studies have investigated the effects of ST6GAL1 on cell phenotype, there is a dearth of knowledge regarding mechanisms that regulate
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A venom peptide-induced NaV channel modulation mechanism involving the interplay between fixed channel charges and ionic gradients. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-09 Ashvriya Thapa,Jia Hao Beh,Samuel D Robinson,Jennifer R Deuis,Hue Tran,Irina Vetter,Angelo Keramidas
Venoms are used by arthropods either to immobilise prey or as defence against predators. Our study focuses on the venom peptide, Ta3a, from the African ant species, Tetramorium africanum and its effects on voltage-gated sodium (NaV) channels, which are ion channels responsible for the generation of electrical signals in electrically excitable cells, such as neurons. Using the NaV1.7 isoform as our
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A novel phospholipase A2 is a core component of the typhoid toxin genetic islet. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-09 Sarah C Gartly,Luke A F Barretto,Anne-Charlotte M T Côté,Zach A Kosowan,Casey C Fowler
S. Typhi, the cause of typhoid fever, is a bacterial pathogen of substantial global importance. Typhoid toxin is a secreted AB-type toxin that is a key S. Typhi virulence factor encoded within a 5-gene genetic islet. Four genes in this islet have well-defined roles in typhoid toxin biology, however the function of the fifth gene is unknown. Here, we investigate the function of this gene, which we name
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A Cub and Sushi domain containing protein with esterase like activity confers insecticide resistance in Indian malaria vector- Anopheles stephensi. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-09 Jatin Kumar,Ankit Kumar,Yash Gupta,Kapil Vashisht,Shivam Kumar,Arvind Sharma,Raj Kumar,Ashoke Sharon,Praveen K Tripathi,Ram Das,Om Prakash Singh,Shailja Singh,Soumyananda Chakraborti,Sujatha Sunil,Kailash C Pandey
Chemical insecticides (organophosphates and pyrethroids) in the form of IRS (Indoor Residual Sprays) and LLINs (Long Lasting insecticidal nets) are the cornerstone for vector control, globally. However, their incessant use has resulted in widespread development of resistance in mosquito vectors, warranting continuous monitoring and investigation of the underlying mechanisms of resistance. Here, we
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Deubiquitinating enzyme USP39 promotes the growth and metastasis of gastric cancer cells by modulating the degradation of RNA-binding protein RBM39. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-09 Chengpiao Lu,Yunxin Cai,Shenglong Wu,Yuhong Wang,Jia-Bin Li,Guoqiang Xu,Jingjing Ma
It has been revealed recently that the RNA-binding motif protein RBM39 is highly expressed in several cancers, which results in poor patient survival. However, how RBM39 is regulated in gastric cancer cells is unknown. Here, affinity purification-mass spectrometry and a biochemical screening are employed to identify the RBM39-interacting proteins and the deubiquitinating enzymes (DUBs) that regulate
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Profiling metabolome of mouse embryonic cerebrospinal fluid following maternal immune activation. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-07 Boryana Petrova,Tiara E Lacey,Andrew J Culhane,Jin Cui,Jeannette R Brook,Alexander Raskind,Aditya Misra,Maria K Lehtinen,Naama Kanarek
The embryonic cerebrospinal fluid (eCSF) plays an essential role in the development of the central nervous system (CNS), influencing processes from neurogenesis to lifelong cognitive functions. An important process affecting eCSF composition is inflammation. Inflammation during development can be studied using the maternal immune activation (MIA) mouse model, which displays altered cytokine eCSF composition
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A "terminal" case of glycan catabolism: structural and enzymatic characterization of the sialidases of Clostridium perfringens. J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-07 Brendon J Medley,Kristin E Low,Jackline D W Irungu,Linus Kipchumba,Parandis Daneshgar,Lin Liu,Jolene M Garber,Leeann Klassen,G Douglas Inglis,Geert-Jan Boons,Wesley F Zandberg,D Wade Abbott,Alisdair B Boraston
Sialic acids are commonly found on the terminal ends of biologically important carbohydrates, including intestinal mucin O-linked glycans. Pathogens such as Clostridium perfringens, the causative agent of necrotic enteritis (NE) in poultry and humans, have the ability to degrade host mucins and colonize the mucus layer, which involves removal of the terminal sialic acid by carbohydrate-active enzymes
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Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-03 Antonio J. Rua, Wayne Mitchell, Steven M. Claypool, Nathan N. Alder, Andrei T. Alexandrescu
Mitochondria are central to cellular metabolism; hence, their dysfunction contributes to a wide array of human diseases. Cardiolipin, the signature phospholipid of the mitochondrion, affects proper cristae morphology, bioenergetic functions, and metabolic reactions carried out in mitochondrial membranes. To match tissue-specific metabolic demands, cardiolipin typically undergoes an acyl tail remodeling
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The rapid-reaction kinetics of an electron-bifurcating flavoprotein, the crotonyl-CoA-dependent NADH:ferredoxin oxidoreductase EtfAB:bcd J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-03 Derek Nguyen, Wayne Vigil Jr., Dimitri Niks, Russ Hille
We have investigated the kinetic behavior of the electron-bifurcating crotonyl-CoA-dependent NADH: ferredoxin oxidoreductase EtfAB:bcd from Megasphaera elsdenii. The overall behavior of the complex in both the reductive and the oxidative half-reactions is consistent with that previously determined for the individual EtfAB and bcd components. This includes an uncrossing of the half-potentials of the
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Rapid small-scale nanobody-assisted purification of ryanodine receptors for cryo-EM J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-02 Chenyao Li, Katrien Willegems, Tomasz Uchański, Els Pardon, Jan Steyaert, Rouslan G. Efremov
Ryanodine receptors (RyRs) are large Ca2+ release channels residing in the endoplasmic or sarcoplasmic reticulum membrane. Three isoforms of RyRs have been identified in mammals, the disfunction of which has been associated with a series of life-threatening diseases. The need for large amounts of native tissue or eukaryotic cell cultures limits advances in structural studies of RyRs. Here, we report
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Translation arrest cancellation of VemP, a secretion monitor in Vibrio, is regulated by multiple cis and trans factors, including SecY J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-02 Yuki Ikeda, Ryoji Miyazaki, Tomoya Tsukazaki, Yoshinori Akiyama, Hiroyuki Mori
VemP is a secretory protein in the Vibrio species that monitors cellular protein-transport activity through its translation arrest, allowing expression of the downstream secD2-secF2 genes in the same operon, which encode components of the protein translocation machinery. When cellular protein-transport function is fully active, secD2/F2 expression remains repressed as VemP translation arrest is canceled
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Crossing the membrane—What does it take to flip a phospholipid? Structural and biochemical advances on P4-ATPase flippases J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-02 Kadambari Vijay Sai, Jyh-Yeuan Lee
Membrane asymmetry is critical for maintenance of several different processes such as cell signaling, apoptosis, and vesicular transport in various eukaryotic systems. Flippases of the P4-ATPase family are associated with flipping phospholipids from the luminal or exoplasmic leaflet to the cytosolic leaflet. P4-ATPases belong to the P-type ATPase family, which are activated by phosphorylation and couple
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TRAF3 regulates STAT6 activation and T-helper cell differentiation by modulating the phosphatase PTP1B J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-02 Tina Arkee, Emma L. Hornick, Gail A. Bishop
The adaptor protein tumor necrosis factor receptor–associated factor 3 (TRAF3) is a multifaceted regulator of lymphocyte biology that plays key roles in modulation of the molecular signals required for T-cell activation and function. TRAF3 regulates signals mediated by the T-cell receptor (TCR), costimulatory molecules, and cytokine receptors, which each drive activation of the serine/threonine kinase
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Inhibition of transient receptor potential vanilloid 3 channels by antimalarial hydroxychloroquine alleviates TRPV3-dependent dermatitis J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-02 Beilei Zhang, Bo Xie, Wen Xu, Dongfan Wei, Li Zhang, Jiayi Sun, Yetan Shi, Jiangfeng Feng, Fan Yang, Heng Zhang, Xiuzu Song
Transient receptor potential vanilloid 3 channel (TRPV3) is closely associated with skin inflammation, but there is a lack of effective and specific inhibitors for clinical use. In this study, we identified antimalarial hydroxychloroquine (HCQ) as a selective TRPV3 inhibitor following the prediction by network pharmacology data analysis. In whole-cell patch-clamp recordings, HCQ inhibited the current
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Alpha-synuclein, autophagy-lysosomal pathway, and Lewy bodies: Mutations, propagation, aggregation, and the formation of inclusions J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-02 Armin Bayati, Peter S. McPherson
Research into the pathophysiology of Parkinson’s disease (PD) is a fast-paced pursuit, with new findings about PD and other synucleinopathies being made each year. The involvement of various lysosomal proteins, such as TFEB, TMEM175, GBA, and LAMP1/2, marks the rising awareness about the importance of lysosomes in PD and other neurodegenerative disorders. This, along with recent developments regarding
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Mycobacterium smegmatis putative Holliday junction resolvases RuvC and RuvX play complementary roles in the processing of branched DNA structures J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-01 Ankit Agarwal, Kalappa Muniyappa
In eubacteria, Holliday junction (HJ) resolvases (HJRs) are crucial for faithful segregation of newly replicated chromosomes, homologous recombination, and repair of stalled/collapsed DNA replication forks. However, compared with the Escherichia coli HJRs, little is known about their orthologs in mycobacterial species. A genome-wide analysis of Mycobacterium smegmatis identified two genes encoding
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Structural analysis of noncanonical translation initiation complexes J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-01 Jacob M. Mattingly, Ha An Nguyen, Bappaditya Roy, Kurt Fredrick, Christine M. Dunham
Translation initiation is a highly regulated, multi-step process that is critical for efficient and accurate protein synthesis. In bacteria, initiation begins when mRNA, initiation factors, and a dedicated initiator fMet-tRNAfMet bind the small (30S) ribosomal subunit. Specific binding of fMet-tRNAfMet in the peptidyl (P) site is mediated by the inspection of the fMet moiety by initiation factor IF2
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KAT tales: Functions of Gcn5 and PCAF lysine acetyltransferases in SAGA and ATAC J. Biol. Chem. (IF 4.0) Pub Date : 2024-09-01 Sharon Y.R. Dent
The Allis group identified Gcn5 as the first transcription-related lysine acetyltransferase in 1996, providing a molecular “missing link” between chromatin organization and gene regulation. This review will focus on functions subsequently identified for Gcn5 and the closely related PCAF protein, in the context of two major complexes, SAGA and ATAC, and how the study of these enzymes informs long standing
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Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2 J. Biol. Chem. (IF 4.0) Pub Date : 2024-08-31 Sivakumar Boopathy, Bridget E. Luce, Camila Makhlouta Lugo, Pusparanee Hakim, Julie McDonald, Ha Lin Kim, Jackeline Ponce, Beatrix M. Ueberheide, Luke H. Chao
Mitochondrial fusion requires the sequential merger of four bilayers to two. The outer-membrane solute carrier family 25 member (SLC25A46) interacts with both the outer and inner membrane dynamin family GTPases mitofusin 1/2 and optic atrophy 1 (Opa1). While SLC25A46 levels are known to affect mitochondrial morphology, how SLC25A46 interacts with mitofusin 1/2 and Opa1 to regulate membrane fusion is
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Identification and characterization of transition metal-binding proteins and metabolites in the phloem sap of Brassica napus J. Biol. Chem. (IF 4.0) Pub Date : 2024-08-31 Hendrik Küpper, Arun Gokul, Dario Alavez, Singha R. Dhungana, Syed Nadeem Hussain Bokhari, Marshall Keyster, David G. Mendoza-Cozatl
Transition metal (TM) distribution through the phloem is an essential part of plant metabolism and is required for systemic signaling and balancing source-to-sink relationships. Due to their reactivity, TMs are expected to occur in complexes within the phloem sap; however, metal speciation in the phloem sap remains largely unexplored. Here, we isolated phloem sap from Brassica napus and analyzed it
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Virus-like particles as robust tools for functional assessment: Deciphering the pathogenicity of ABCA4 genetic variants of uncertain significance J. Biol. Chem. (IF 4.0) Pub Date : 2024-08-31 Senem Cevik, Subhasis B. Biswas, Arit Ghosh, Esther E. Biswas-Fiss
The retina-specific ABCA transporter, ABCA4, is essential for vision, and its genetic variants are associated with a wide range of inherited retinal degenerative diseases, leading to blindness. Of the 1630 identified missense variants in ABCA4, ∼50% are of unknown pathogenicity (variants of unknown significance, VUS). This genetic uncertainty presents three main challenges: (i) inability to predict