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p38 MAPK-dependent phosphorylation of transcription factor SOX2 promotes an adaptive response to BRAF inhibitors in melanoma cells J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-07 Silvia Pietrobono, Raffaella De Paolo, Domenico Mangiameli, Andrea Marranci, Ilaria Battisti, Cinzia Franchin, Giorgio Arrigoni, Davide Melisi, Laura Poliseno, Barbara Stecca
Despite recent advances in the development of BRAF kinase inhibitors (BRAFi) for BRAF-mutant melanomas, development of resistance remains a major clinical problem. In addition to genetic alterations associated with intrinsic resistance, several adaptive response mechanisms are known to be rapidly activated to allow cell survival in response to treatment, limiting efficacy. A better understanding of
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The structure and characterization of human cytochrome P450 8B1 supports future drug design for non-alcoholic fatty liver disease and diabetes J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-06 Jinghan Liu, Heather A. Carlson, Emily E. Scott
Human cytochrome P450 8B1 (CYP8B1) is involved in conversion of cholesterol to bile acids. It hydroxylates the steroid ring at C12 to produce the bile acid cholic acid. Studies implicated this enzyme as a good drug target for nonalcoholic fatty liver disease and type 2 diabetes, but there are no selective inhibitors known for this enzyme and no structures to guide inhibitor development. Herein the
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Enzymatic Dispersion of Biofilms: An Emerging Biocatalytic Avenue to Combat Biofilm-Mediated Microbial Infections J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-06 Reshma Ramakrishnan, Ashish Kumar Singh, Simran Singh, Dipshikha Chakravortty, Debasis Das
Drug resistance by pathogenic microbes has emerged as a matter of great concern to mankind. Microorganisms such as bacteria and fungi employ multiple defense mechanisms against drugs and the host immune system. A major line of microbial defense is the biofilm, which comprises extracellular polymeric substances (EPS) that are produced by the population of microorganisms. Around 80% of chronic bacterial
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G protein-coupled receptor kinase phosphorylation of distal C-tail sites specifies βarrestin1-mediated signaling by chemokine receptor CXCR4 J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-06 Ya Zhuo, Joseph M. Crecelius, Adriano Marchese
G protein‐coupled receptor (GPCR) kinases (GRKs) and arrestins mediate GPCR desensitization, internalization, and signaling. The spatial pattern of GPCR phosphorylation is predicted to trigger these discrete GRK and arrestin-mediated functions. Here, we provide evidence that distal carboxyl-terminal tail (C-tail), but not proximal, phosphorylation of the chemokine receptor CXCR4 specifies ßarrestin1
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An intrinsically disordered transcription activation domain increases the DNA binding affinity and reduces the specificity of NFκB p50/RelA J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-05 Hannah E.R. Baughman, Dominic Narang, Wei Chen, Amalia C. Villagrán Suárez, Joan Lee, Maxwell J. Bachochin, Tristan R. Gunther, Peter G. Wolynes, Elizabeth A. Komives
Many transcription factors contain intrinsically disordered transcription activation domains (TADs), which mediate interactions with co-activators to activate transcription. Historically, DNA-binding domains and TADs have been considered as modular units, but recent studies have shown that TADs can influence DNA binding. Whether these results can be generalized to more TADs is not clear. Here we biophysically
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The 5′-phosphate enhances the DNA-binding and exonuclease activities of human mitochondrial genome maintenance nuclease 1 (MGME1) J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-05 Kathleen M. Urrutia, Wenyan Xu, Linlin Zhao
In higher eukaryotes, mitochondria play multiple roles in energy production, signaling, and biosynthesis. Mitochondria possess multiple copies of mitochondrial DNA (mtDNA), which encodes 37 genes that are essential for mitochondrial and cellular function. When mtDNA is challenged by endogenous and exogenous factors, mtDNA undergoes repair, degradation, and compensatory synthesis. mtDNA degradation
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The SOS response-associated peptidase (SRAP) domain of YedK catalyzes ring opening of abasic sites and reversal of its DNA-protein crosslink J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-05 Katherine A. Paulin, David Cortez, Brandt F. Eichman
Apurinic/apyrimidinic (AP, or abasic) sites in DNA are one of the most common forms of DNA damage. AP sites are reactive and form crosslinks to both proteins and DNA, are prone to strand breakage, and inhibit DNA replication and transcription. The replication-associated AP site repair protein HMCES protects cells from strand breaks, inhibits mutagenic translesion synthesis, and participates in repair
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Two types of peptides derived from the neurotoxin GsMTx4 inhibit a mechanosensitive potassium channel by modifying the mechano-gate J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-04 Nan Zhou, Hui Li, Jie Xu, Zhong-Shan Shen, Mingxi Tang, Xiao-Hui Wang, Wan-Xin Su, Masahiro Sokabe, Zhe Zhang, Qiong-Yao Tang
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans. Current AF antiarrhythmic drugs have limited efficacy and carry the risk of ventricular pro-arrhythmia. GsMTx4, a mechanosensitive channel (MSC)-selective inhibitor, has been shown to suppress arrhythmias through the inhibition of stretch-activated channels (SACs) in the heart. The cost of synthesizing this peptide
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Isoforms of GPR35 have distinct extracellular N-termini that allosterically modify receptor-transducer coupling and mediate intracellular pathway bias J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-04 Hannes Schihada, Thomas M. Klompstra, Laura J. Humphrys, Igor Cervenka, Shamim Dadvar, Peter Kolb, Jorge L. Ruas, Gunnar Schulte
Within the intestine, the human G protein-coupled receptor (GPCR) GPR35 is involved in oncogenic signaling, bacterial infections, and inflammatory bowel disease. GPR35 is known to be expressed as two distinct isoforms that differ only in the length of their extracellular N-termini by 31 amino acids, but detailed insights into their functional differences are lacking. Through gene expression analysis
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Dynamic S-acylation of the ER-resident protein stromal interaction molecule 1 (STIM1) is required for store-operated Ca2+ entry J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-04 Goutham Kodkandla, Savannah J. West, Qiaochu Wang, Ritika Tewari, Michael X. Zhu, Askar M. Akimzhanov, Darren Boehning
Many cell surface stimuli cause calcium release from endoplasmic reticulum (ER) stores to regulate cellular physiology. Upon ER calcium store depletion, the ER-resident protein stromal interaction molecule 1 (STIM1) physically interacts with plasma membrane protein Orai1 to induce calcium release-activated calcium (CRAC) currents that conduct calcium influx from the extracellular milieu. Although the
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Alkaline pH has an unexpected effect on transcriptional pausing during synthesis of the E. coli pH-responsive riboswitch J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-04 Christine Stephen, Tatiana V. Mishanina
Riboswitches are 5’-untranslated regions of mRNA that change their conformation in response to ligand binding, allowing post-transcriptional gene regulation. This ligand-based model of riboswitch function has been expanded with the discovery of a “pH-responsive element” (PRE) riboswitch in E. coli. At neutral pH, the PRE folds into a translationally inactive structure with an occluded ribosome binding
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Progranulin-derived granulin E and lysosome membrane protein CD68 interact to reciprocally regulate their protein homeostasis J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-04 Mariela Nunez Santos, Daniel H. Paushter, Tingting Zhang, Xiaochun Wu, Tuancheng Feng, Jiaoying Lou, Huan Du, Stephanie M. Becker, Robert Fragoza, Haiyuan Yu, Fenghua Hu
Progranulin (PGRN) is a glycoprotein implicated in several neurodegenerative diseases. It is highly expressed in microglia and can be secreted or delivered to the lysosome compartment. PGRN comprises 7.5 granulin repeats and is processed into individual granulin peptides within the lysosome, but the functions of these peptides are largely unknown. Here, we identify CD68, a lysosome membrane protein
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The ARSACS disease protein sacsin controls lysosomal positioning and reformation by regulating microtubule dynamics J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-04 Vincent Francis, Walaa Alshafie, Rahul Kumar, Martine Girard, Bernard Brais, Peter S. McPherson
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a fatal brain disorder featuring cerebellar neurodegeneration leading to spasticity and ataxia. ARSACS is caused by mutations in the SACS gene that encodes sacsin, a massive 4579-amino acid protein with multiple modular domains. However, molecular details of the function of sacsin are not clear. Here using time lapse imaging and
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Biased GPCR signaling by the native parathyroid hormone-related protein 1–141 relative to its N-terminal fragment 1–36 J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-04 Karina A. Peña, Alex D. White, Sofya Savransky, Ignacio Portales Castillo, Frédéric G. Jean-Alphonse, Thomas J. Gardella, Ieva Sutkeviciute, Jean-Pierre Vilardaga
The parathyroid hormone (PTH)-related protein (PTHrP) is indispensable for the development of mammary glands, placental calcium ion transport, tooth eruption, bone formation and bone remodeling, and causes hypercalcemia in patients with malignancy. Although mature forms of PTHrP in the body consist of splice variants of 139, 141 and 173 amino acids, our current understanding on how endogenous PTHrP
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Oxygen-dependent regulation of E3(SCF)ubiquitin ligases and a Skp1-associated JmjD6 homolog in development of the social amoeba Dictyostelium J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-04 Andrew W. Boland, Elisabet Gas-Pascual, Braxton L. Nottingham, Hanke van der Wel, M. Osman Sheikh, Christopher M. Schafer, Christopher M. West
E3-SCF (Skp1/cullin-1/F-box protein) polyubiquitin ligases activate the proteasomal degradation of over a thousand proteins, but the evolutionary diversification of the F-box protein (FBP) family of substrate receptor subunits has challenged their elucidation in protists. Here we expand the FBP candidate list in the social amoeba Dictyostelium and show that the Skp1 interactome is highly remodeled
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A conserved sequence motif in the E. coli soluble FAD-containing pyridine nucleotide transhydrogenase is important for reaction efficiency J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-04 Michele Partipilo, Guang Yang, Maria Laura Mascotti, Hein J. Wijma, Dirk Jan Slotboom, Marco W. Fraaije
Soluble pyridine nucleotide transhydrogenases (STHs) are flavoenzymes involved in the redox homeostasis of the essential cofactors NAD(H) and NADP(H). They catalyze the reversible transfer of reducing equivalents between the two nicotinamide cofactors. The soluble transhydrogenase from Escherichia coli (SthA) has found wide use in both in vivo and in vitro applications to steer reducing equivalents
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Temperature-dependent hydrogen deuterium exchange shows impact of analog binding on adenosine deaminase flexibility but not embedded thermal networks J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-04 Shuaihua Gao, Wenju Zhang, Samuel L. Barrow, Anthony T. Iavarone, Judith P. Klinman
The analysis of hydrogen deuterium exchange by mass spectrometry as a function of temperature and mutation (TDHDX-MS) has emerged as a generic and efficient tool for the spatial resolution of protein networks that are proposed to function in the thermal activation of catalysis. In this work, we extend TDHDX from apo-enzyme structures to protein-ligand complexes. Using adenosine deaminase as a prototype
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Transcriptional coregulator Ess2 controls survival of post-thymic CD4+ T cells through the Myc and IL-7 signaling pathways J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-03 Ichiro Takada, Shinya Hidano, Sayuri Takahashi, Kaori Yanaka, Hidesato Ogawa, Megumi Tsuchiya, Atsushi Yokoyama, Shingo Sato, Hiroki Ochi, Tohru Nakagawa, Takashi Kobayashi, Shinichi Nakagawa, Makoto Makishima
Ess2, also known as Dgcr14, is a transcriptional co-regulator of CD4+ T cells. Ess2 is located in a chromosomal region, the loss of which has been associated with 22q11.2 deletion syndrome (22q11DS), which causes heart defects, skeletal abnormalities and immunodeficiency. However, the specific association of Ess2 with 22q11DS remains unclear. To elucidate the role of Ess2 in T-cell development, we
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Importance of RNA length for in vitro encapsidation by the nucleoprotein of human Respiratory Syncytial Virus J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-03 Lorène Gonnin, Charles-Adrien Richard, Irina Gutsche, Didier Chevret, Joris Troussier, Jean-Jacques Vasseur, Françoise Debart, Jean-François Eléouët, Marie Galloux
Respiratory syncytial virus (RSV) has a negative-sense single-stranded RNA genome constitutively encapsidated by the viral nucleoprotein N, forming a helical nucleocapsid which is the template for viral transcription and replication by the viral polymerase L. Recruitment of L onto the nucleocapsid depends on the viral phosphoprotein P, which is an essential L cofactor. A prerequisite for genome and
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The secondary pocket of Cryptochrome 2 is important for the regulation of its stability and localization J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-03 Gizem Cagla Parlak, Bilge Bahar Camur, Seref Gul, Onur Ozcan, Ibrahim Baris, Ibrahim Halil Kavakli
Human clock-gene variations contribute to the phenotypic differences observed in various behavioral and physiological processes such as diurnal preference, sleep, metabolism, mood regulation, addiction, and fertility. However, little is known about the possible effects of identified variations at the molecular level. In this study, we performed a functional characterization at the cellular level of
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Depletion of endogenously biotinylated carboxylases enhances the sensitivity of TurboID-mediated proximity labeling in C. elegans J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-03 Murat Artan, Markus Hartl, Weiqiang Chen, Mario de Bono
Proximity-dependent protein labeling provides a powerful in vivo strategy to characterize the interactomes of specific proteins. We previously optimized a proximity labeling protocol for C. elegans using the highly active biotin ligase TurboID. A significant constraint on the sensitivity of TurboID is the presence of abundant, endogenously biotinylated proteins that take up bandwidth in the mass spectrometer
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O-GlcNAcylation stabilizes the autophagy-initiating kinase ULK1 by inhibiting chaperone-mediated autophagy upon HPV infection J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-03 Yingxin Shi, Sheng Yan, Guang-Can Shao, Jinglong Wang, Yong-Ping Jian, Bo Liu, Yanqiu Yuan, Ke Qin, Shanshan Nai, Xiahe Huang, Yingchun Wang, Zhenghui Chen, Xing Chen, Meng-Qiu Dong, Yiqun Geng, Zhi-Xiang Xu, Jing Li
Human papillomaviruses (HPVs) cause a subset of cases of head and neck squamous cell carcinomas (HNSCCs). Previously, we demonstrated that HPV16 oncogene E6 or E6/E7 transduction increases the abundance of O-linked GlcNAcylation (O-GlcNAc) transferase (OGT), but the OGT substrates and cellular pathways affected by this increase are unclear. Here, we focus on the effects of O-GlcNAcylation on HPV-positive
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EGF promotes PKM2 O-GlcNAcylation by stimulating O-GlcNAc transferase phosphorylation at Y976 and their subsequent association J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-03 Yang Wang, Hengyao Shu, Jia Liu, Xin Jin, Lihua Wang, Yanzhao Qu, Mingjie Xia, Pinghui Peng, Yunpeng Feng, Min Wei
Epidermal growth factor (EGF) is one of the most well-characterized growth factors and plays a crucial role in cell proliferation and differentiation. Its receptor EGFR has been extensively explored as a therapeutic target against multiple types of cancers, such as lung cancer and glioblastoma. Recent studies have established a connection between deregulated EGF signaling and metabolic reprogramming
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An immunogenic cell injury module for the single-cell multiplexed activity metabolomics platform to identify promising anti-cancer natural products J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-02 Joseph A. Balsamo, Kathryn E. Penton, Zhihan Zhao, Madeline J. Hayes, Sierra M. Lima, Jonathan M. Irish, Brian O. Bachmann
Natural products constitute and significantly impact many current anti-cancer medical interventions. A subset of natural products induces injury processes in malignant cells that recruit and activate host immune cells to produce an adaptive anti-cancer immune response, a process known as immunogenic cell death. However, a challenge in the field is to delineate forms of cell death and injury that best
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Chlamydia trachomatis development requires both host glycolysis and oxidative phosphorylation but has only minor effects on these pathways J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-02 Maimouna D. N’Gadjaga, Stéphanie Perrinet, Michael G. Connor, Giulia Bertolin, Gaël A. Millot, Agathe Subtil
The obligate intracellular bacteria Chlamydia trachomatis obtain all nutrients from the cytoplasm of their epithelial host cells and stimulate glucose uptake by these cells. They even hijack host ATP, exerting a strong metabolic pressure on their host at the peak of the proliferative stage of their developmental cycle. However, it is largely unknown whether infection modulates the metabolism of the
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Dioxin-elicited decrease in cobalamin redirects propionyl-CoA metabolism to the β–oxidation-like pathway, resulting in acrylyl-CoA conjugate buildup J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-02 Karina Orlowska, Russ R. Fling, Rance Nault, Warren J. Sink, Anthony L. Schilmiller, Tim Zacharewski
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant that induces diverse biological and toxic effects, including reprogramming intermediate metabolism, mediated by the aryl hydrocarbon receptor (AHR). However, the specific reprogramming effects of TCDD are unclear. Here, we performed targeted LC-MS analysis of hepatic extracts from mice gavaged with TCDD. We detected
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Maternal high cholesterol diet negatively programs offspring bone development and downregulates hedgehog signaling in osteoblasts J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-02 SVVS Ravi Mangu, Kalpana Patel, Shinde Vijay Sukhdeo, M.R. Savitha, Kunal Sharan
Cholesterol is one of the essential intrauterine factors required for fetal growth and development. Maternal high cholesterol levels are known to be detrimental for offspring health. However, its long-term effect on offspring skeletal development remains to be elucidated. We performed our studies in two strains of mice (C57BL6/J and Swiss Albino) and human subjects (65 mother-female newborn dyads)
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Proto-oncogene FAM83A contributes to casein kinase 1-mediated mitochondrial maintenance and white adipocyte differentiation J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-02 Kuilong Huang, Zhihao Jia, Haoran Li, Ying Peng, Xiaochang Chen, Nanjian Luo, Tongxing Song, Yingqian Wang, Xin’e Shi, Shihuan Kuang, Gongshe Yang
Family with sequence similarity 83 A (FAM83A) is a newly discovered proto-oncogene that has been shown to play key roles in various cancers. However, the function of FAM83A in other physiological processes is not well known. Here, we report a novel function of FAM83A in adipocyte differentiation. We used an adipocyte-targeting fusion-oligopeptide (FITC-ATS-9R) to deliver a FAM83A-sgRNA/Cas9 plasmid
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A short amphipathic alpha helix in scavenger receptor BI facilitates bidirectional HDL-cholesterol transport J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-01 Sarah C. May, Daisy Sahoo
During reverse cholesterol transport, HDL carries excess cholesterol from peripheral cells to the liver for excretion in bile. The first and last steps of this pathway involve the HDL receptor, scavenger receptor BI (SR-BI). While the mechanism of SR-BI-mediated cholesterol transport has not yet been established, it has long been suspected that cholesterol transport occurs through a hydrophobic tunnel
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Correction: Schizosaccharomyces pombe Ppr10 and Mpa1 together mediate mitochondrial translational initiation J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-03 Ying Luo, Yirong Wang, Ying Huang
Abstract not available
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The Na,K-ATPase in complex with beryllium fluoride mimics an ATPase phosphorylated state. J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-02 Marlene U. Fruergaard, Ingrid Dach, Jacob L. Andersen, Mette Ozol, Azadeh Shasavar, Esben M. Quistgaard, Hanne Poulsen, Natalya U. Fedosova, Poul Nissen
The Na+,K+-ATPase generates electrochemical gradients of Na+ and K+ across the plasma membrane via a functional cycle that includes various phosphoenzyme intermediates. However, the structure and function of these intermediates and how metal fluorides mimick them require further investigation. Here, we describe a 4.0 Å resolution crystal structure and functional properties of the pig kidney Na+,K+-ATPase
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Homeodomain-interacting protein kinase HIPK4 regulates phosphorylation of manchette protein RIMBP3 during spermiogenesis J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-02 Xiaofei Liu, Chunyan Zang, Yifei Wu, Ru Meng, Yu Chen, Tao Jiang, Cheng Wang, Xiaoyu Yang, Yueshuai Guo, Chenghao Situ, Zhibin Hu, Jun Zhang, Xuejiang Guo
Nonobstructive azoospermia (NOA) is the most serious form of spermatogenesis abnormalities in male infertility. Genetic factors are important to consider as elements leading to NOA. Although many pathogenic genes have been reported, the causative genes of NOA for many patients are still unknown. In this study, we found ten point mutations in the gene encoding homeodomain-interacting protein kinase
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A new fluorescent sensor mitoferrofluor indicates the presence of chelatable iron in polarized and depolarized mitochondria J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-02 Andaleb Kholmukhamedov, Li Li, Christopher C. Lindsey, Jiangting Hu, Anna-Liisa Nieminen, Kenji Takemoto, Gyda C. Beeson, Chad M. Beneker, Campbell McInnes, Craig C. Beeson, John J. Lemasters
Mitochondrial chelatable iron contributes to the severity of several injury processes, including ischemia/reperfusion, oxidative stress, and drug toxicity. However, methods to measure this species in living cells are lacking. To measure mitochondrial chelatable iron in living cells, here we synthesized a new fluorescent indicator, mitoferrofluor (MFF). We designed cationic MFF to accumulate electrophoretically
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Dynamics of integrin α5β1, fibronectin, and their complex reveal sites of interaction and conformational change J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-02 Yang Su, Roxana E. Iacob, Jing Li, John R. Engen, Timothy A. Springer
Integrin α5β1 mediates cell adhesion to the extracellular matrix (ECM) by binding fibronectin (Fn). Selectivity for Fn by α5β1 is achieved through recognition of an RGD motif in the 10th type-III Fn domain (Fn10) and the synergy site in the 9th type-III Fn domain (Fn9). However, details of the interaction dynamics are unknown. Here, we compared synergy-site and Fn-truncation mutations for their α5β1-binding
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Ubiquitin-specific protease TRE17/USP6 promotes tumor cell invasion through the regulation of glycoprotein CD147 intracellular trafficking J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-02 Yukino Ogura, Norihiko Ohbayashi, Yasunori Kanaho, Atsushi Kawaguchi, Yuji Funakoshi
Disordered expression and distribution of plasma membrane proteins at the cell surface leads to diverse malignant phenotypes in tumors, including cell invasion. The ubiquitin-specific protease TRE17/USP6, an oncogene identified in Ewing sarcoma, is highly expressed in several cancers and locally aggressive tumor-like lesions. We have previously demonstrated that TRE17 regulates the trafficking of plasma
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Cyclin-dependent kinase-mediated phosphorylation and the negative regulatory domain of transcription factor B-Myb modulate its DNA binding J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-01 Tilini U. Wijeratne, Keelan Z. Guiley, Hsiau-Wei Lee, Gerd A. Müller, Seth M. Rubin
B-Myb is a highly conserved member of the vertebrate Myb family of transcription factors that plays a critical role in cell-cycle progression and proliferation. Myb proteins activate Myb-dependent promoters by interacting specifically with Myb binding site (MBS) sequences using their DNA binding domain (DBD). Transactivation of MBS promoters by B-Myb is repressed by its negative regulatory domain (NRD)
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Induction of zinc finger protein RNF6 auto-ubiquitination for the treatment of myeloma and chronic myeloid leukemia J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-01 Haixia Zhuang, Ying Ren, Chenyu Mao, Yueya Zhong, Zubin Zhang, Biyin Cao, Yuming Zhang, Jinqi Huang, Guoqiang Xu, Zhenqian Huang, Yujia Xu, Xinliang Mao
The zinc finger ubiquitin ligase RNF6 has been proposed as a potential therapeutic target in several cancers, but understanding its molecular mechanism of degradation has been elusive. In the present study, we find that RNF6 is degraded via auto-ubiquitination in a manner dependent on its Really Interesting New Gene (RING) domain. We determine that when the RING domain is deleted (ΔRING) or the core
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Extracellular loop 2 of G protein-coupled olfactory receptors is critical for odorant recognition J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-01 Yiqun Yu, Zhenjie Ma, Jody Pacalon, Lun Xu, Weihao Li, Christine Belloir, Jeremie Topin, Loïc Briand, Jérôme Golebiowski, Xiaojing Cong
G protein-coupled olfactory receptors (ORs) enable us to detect innumerous odorants. They are also ectopically expressed in non-olfactory tissues and emerging as attractive drug targets. ORs can be promiscuous or highly specific, which is part of a larger mechanism for odor discrimination. Here, we demonstrate that the OR extracellular loop 2 (ECL2) plays critical roles in OR promiscuity and specificity
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Loss of myeloid lipoprotein lipase exacerbates adipose tissue fibrosis with collagen VI deposition and hyperlipidemia in leptin-deficient obese mice J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-01 Manabu Takahashi, Daisuke Yamamuro, Tetsuji Wakabayashi, Akihito Takei, Shoko Takei, Shuichi Nagashima, Hiroaki Okazaki, Ken Ebihara, Hiroaki Yagyu, Yuki Takayanagi, Tatsushi Onaka, Ira J. Goldberg, Shun Ishibashi
During obesity, tissue macrophages increase in number and become pro-inflammatory, thereby contributing to metabolic dysfunction. Lipoprotein lipase (LPL), which hydrolyzes triglyceride (TG) in lipoproteins, is secreted by macrophages. However, the role of macrophage-derived LPL in adipose tissue remodeling and lipoprotein metabolism is largely unknown. To clarify these issues, we crossed leptin-deficient
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Interactions between mTORC2 core subunits Rictor and mSin1 dictate selective and context-dependent phosphorylation of substrate kinases SGK1 and Akt. J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-01 Zanlin Yu, Junliang Chen, Enzo Takagi, Feng Wang, Bidisha Saha, Xi Liu, Lydia-Marie Joubert, Catherine E. Gleason, Mingliang Jin, Chengmin Li, Carlos Nowotny, David Agard, Yifan Cheng, David Pearce
Mechanistic target of rapamycin complex 2 (mTORC2) is a multi-subunit kinase complex, central to multiple essential signaling pathways. Two core subunits, Rictor and mSin1, distinguish it from the related mTORC1 and support context-dependent phosphorylation of its substrates. mTORC2 structures have been determined previously, however, important questions remain, particularly regarding the structural
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Whole cell response to receptor stimulation involves many deep and distributed subcellular biochemical processes J. Biol. Chem. (IF 5.486) Pub Date : 2022-08-01 Jens Hansen, Mustafa M. Siddiq, Arjun Singh Yadaw, Rosa E. Tolentino, Vera Rabinovich, Gomathi Jayaraman, Mohit Raja Jain, Tong Liu, Hong Li, Yuguang Xiong, Joseph Goldfarb, Ravi Iyengar
Neurite outgrowth is an integrated whole-cell response triggered by the cannabinoid-1 receptor (CB1R). We sought to identify the many different biochemical pathways that contribute to this whole cell response. To understand underlying mechanisms, we identified subcellular processes composed of one or more biochemical pathways and their interactions required for this response. Differentially expressed
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Contribution of the EssC ATPase to the assembly of the type 7b secretion system in Staphylococcus aureus J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-31 Maksym Bobrovskyy, So Young Oh, Dominique Missiakas
Secretion systems often utilize ATPase activity to facilitate the translocation of proteins into and across membranes. In bacteria, the universally conserved SecA ATPase binds a large repertoire of preproteins and interacts with the SecYEG translocon. In contrast, the type 7b secretion system (T7bSS) of Staphylococcus aureus supports the secretion of a restricted subset of proteins. T7bSSs are found
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Unusual β1-4-galactosidase activity of an α1-6-mannosidase from Xanthomonas manihotis in the processing of branched hybrid and complex glycans J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-31 Yi-Min She, Kody Klupt, Grayson Hatfield, Zongchao Jia, Roger Y. Tam
Mannosidases are a diverse group of glycoside hydrolases that play crucial roles in mannose trimming of oligomannose glycans, glycoconjugates, and glycoproteins involved in numerous cellular processes, such as glycan biosynthesis and metabolism, structure regulation, cellular recognition, and cell-pathogen interactions. Exo- and endo-mannosidases cleave specific glycosidic bonds of mannoside linkages
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Chemically-modified dsRNA induces RNAi effects in insects in vitro and in vivo: A potential new tool for improving RNA-based plant protection. J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-31 John D. Howard, Myriam Beghyn, Nathalie Dewulf, Yves De Vos, Annelies Philips, David Portwood, Peter M. Kilby, Duncan Oliver, Wendy Maddelein, Stephen Brown, Mark J. Dickman
Global agriculture loses over $100 billion of produce annually to crop pests such as insects. Many of these crop pests either are not currently controlled by artificial means or have developed resistance against chemical pesticides. Long dsRNAs are capable of inducing RNA interference (RNAi) in insects and are emerging as novel, highly selective alternatives for sustainable insect management strategies
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Meeting report: Flux-independent signaling by ionotropic receptors: unforeseen roles, complexities, and challenges. J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-31 Pavel Montes de Oca Balderas
Abstract not available
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Increasing Access for Biochemistry Research in Undergraduate Education: the Malate Dehydrogenase CURE Community J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-31 Joseph J. Provost
Integrating research into the classroom environment is an influential pedagogical tool to support student learning, increase retention of STEM students, and help students identify as scientists. The evolution of course-based undergraduate research experiences (CUREs) has grown from individual faculty incorporating their research in the teaching laboratory into well-supported systems to sustain faculty
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Butyrate inhibits IL-1β-induced inflammatory gene expression by suppression of NF-κB activity in pancreatic beta cells J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-31 Signe Schultz Pedersen, Michala Prause, Kristine Williams, Romain Barrès, Nils Billestrup
Cytokine-induced beta cell dysfunction is a hallmark of type 2 diabetes (T2D). Chronic exposure of beta cells to inflammatory cytokines alters gene expression and impairs insulin secretion. Thus, identification of anti-inflammatory factors that preserve beta cell function represents an opportunity to prevent or treat T2D. Butyrate is a gut microbial metabolite with anti-inflammatory properties for
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Protein arginine methyltransferase PRMT1 promotes adipogenesis by modulating transcription factors C/EBPβ and PPARγ J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-31 Qi Zhu, Dinghui Wang, Feng Liang, Xian Tong, Ziyun Liang, Xiaoyu Wang, Yaosheng Chen, Delin Mo
Protein arginine methyltransferase 1 (PRMT1) methylates a variety of histone and non-histone protein substrates to regulate multiple cellular functions such as transcription, DNA damage response, and signal transduction. It has been reported as an emerging regulator of various metabolic pathways including glucose metabolism in the liver, atrophy in the skeletal muscle, and lipid catabolism in the adipose
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Cleavage of mitochondrial homeostasis regulator PGAM5 by the intramembrane protease PARL is governed by transmembrane helix dynamics and oligomeric state J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-31 Verena Siebert, Mara Silber, Elena Heuten, Claudia Muhle-Goll, Marius K. Lemberg
The intramembrane protease PARL acts as a crucial mitochondrial safeguard by cleaving the mitophagy regulators PINK1 and PGAM5. Depending on the stress level, PGAM5 can either stimulate cell survival or cell death. In contrast to PINK1, which is constantly cleaved in healthy mitochondria and only active when the inner mitochondrial membrane is depolarized, PGAM5 processing is inversely regulated. However
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The weaker-binding Fc γ receptor IIIa F158 allotype retains sensitivity to N-glycan composition and exhibits a destabilized antibody-binding interface J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-31 Paul G. Kremer, Adam W. Barb
Antibodies engage Fc γ Receptors (FcγRs) to elicit healing cellular immune responses following binding to a target antigen. FcγRIIIa / CD16a triggers natural killer cells to destroy target tissues with cytotoxic proteins and enhances phagocytosis mediated by macrophages. Multiple variables affect CD16a antibody binding strength and the resulting immune response, including a genetic polymorphism. The
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MAP3K4 promotes fetal and placental growth by controlling the receptor tyrosine kinases IGF1R/IR and Akt signaling pathway† J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-31 Charles H. Perry, Nathan A. Mullins, Razan B.A. Sweileh, Noha A.M. Shendy, Patrick A. Roberto, Amber L. Broadhurst, Hannah A. Nelson, Gustavo A. Miranda-Carboni, Amy N. Abell
Disruption of fetal growth results in severe consequences to human health, including increased fetal and neonatal morbidity and mortality, as well as potential lifelong health problems. Molecular mechanisms promoting fetal growth represent potential therapeutic strategies to treat and/or prevent fetal growth restriction (FGR). Here we identify a previously unknown role for the mitogen-activated protein
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Secretagogin is a Ca2+-dependent stress-responsive chaperone that may also play a role in aggregation-based proteinopathies J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-21 Amrutha H. Chidananda, Radhika Khandelwal, Aditya Jhamkhindikar, Asmita D. Pawar, Anand K. Sharma, Yogendra Sharma
Secretagogin (SCGN) is a three-domain hexa-EF-hand Ca2+-binding protein that plays a regulatory role in the release of several hormones. SCGN is expressed largely in pancreatic β-cells, certain parts of the brain, and also in neuroendocrine tissues. The expression of SCGN is altered in several diseases, such as diabetes, cancers, and neurodegenerative disorders; however, the precise associations that
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Prostaglandin F2α and angiotensin II type 1 receptors exhibit differential cognate G protein coupling regulation J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-21 Dana Sedki, Aaron Cho, Yubo Cao, Ljiljana Nikolajev, N. D. Prasad Atmuri, William D. Lubell, Stéphane A. Laporte
Promiscuous G protein-coupled receptors (GPCRs) engage multiple Gα subtypes with different efficacies to propagate signals in cells. A mechanistic understanding of Gα selectivity by GPCRs is critical for therapeutic design, since signaling can be restrained by ligand–receptor complexes to preferentially engage specific G proteins. However, details of GPCR selectivity are unresolved. Here, we investigated
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EPDR1 is a Non-canonical Effector of Insulin-mediated Angiogenesis Regulated by an Endothelial-specific TGF-β Receptor Complex J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-21 Tasmia Ahmed, Paola Cruz Flores, Christopher C. Pan, Hannah R. Ortiz, Yeon S. Lee, Paul R. Langlais, Karthikeyan Mythreye, Nam Y. Lee
Insulin signaling in blood vessels primarily functions to stimulate angiogenesis and maintain vascular homeostasis through the canonical PI3K and MAPK signaling pathways. However, angiogenesis is a complex process coordinated by multiple other signaling events. Here we report a distinct crosstalk between the insulin receptor (IR) and endoglin/activin receptor-like kinase 1 (ALK1), an endothelial cell
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CaMKII T286 phosphorylation has distinct essential functions in three forms of long-term plasticity J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-21 Sarah G. Cook, Nicole L. Rumian, K. Ulrich Bayer
The Ca2+/calmodulin-dependent protein kinase II (CaMKII) mediates long-term potentiation or depression (LTP or LTD) after distinct stimuli of hippocampal NMDA-type glutamate receptors (NMDARs). NMDAR-dependent LTD prevails in juvenile mice, but a mechanistically different form of LTD can be readily induced in adults by instead stimulating metabotropic glutamate receptors (mGluRs). However, the role
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Myosin light chain phosphatase catalytic subunit dephosphorylates cardiac myosin via mechanisms dependent and independent of the MYPT regulatory subunits J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-21 Eunyoung Lee, Zhenan Liu, Nhu Nguyen, Angus Nairn, Audrey N. Chang
Cardiac muscle myosin regulatory light chain (RLC) is constitutively phosphorylated at ∼0.4 mol phosphate/mol RLC in normal hearts, and phosphorylation is maintained by balanced activities of dedicated cardiac muscle-specific myosin light chain kinase (MLCK) and phosphatase (MLCP). Previously, the identity of the cardiac-MLCP was biochemically shown to be similar to the smooth muscle MLCP, which is
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HMGN2 represses gene transcription via interaction with transcription factors Lef-1 and Pitx2 during amelogenesis J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-21 Steven Eliason, Dan Su, Flavia Pinho, Zhao Sun, Zichao Zhang, Xiao Li, Mason Sweat, Shankar R. Venugopalan, Bing He, Michael Bustin, Brad A. Amendt
The chromatin-associated high mobility group protein N2 (HMGN2) co-factor regulates transcription factor activity through both chromatin and protein interactions. Hmgn2 expression is known to be developmentally regulated, but the post-transcriptional mechanisms that regulate Hmgn2 expression and its precise roles in tooth development remain unclear. Here, we demonstrate that HMGN2 inhibits the activity
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O-GlcNAc tranferase regulates p21 protein levels and cell proliferation through the FoxM1-Skp2 axis in a p53-independent manner J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-20 Rafaela Muniz de Queiroz, Sung-Hwan Moon, Carol Prives
The protein product of the CDKN1A gene, p21, has been extensively characterized as a negative regulator of the cell cycle. Nevertheless, it is clear that p21 has manifold complex and context-dependent roles that can be either tumor suppressive or oncogenic. Most well-studied as a transcriptional target of the p53 tumor suppressor protein, there are other means by which p21 levels can be regulated.
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Multiple knockout mouse and embryonic stem cell models reveal the role of miR-124a in neuronal maturation J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-20 Taro Chaya, Maeda Yamato, Ryo Sugimura, Daisuke Okuzaki, Satoshi Watanabe, Leah R. Varner, Daisuke Motooka, Daichi Gyoten, Haruka Yamamoto, Hidemasa Kato, Takahisa Furukawa
MicroRNA-124a (miR-124a) is one of the most abundantly expressed microRNAs in the central nervous system (CNS) and is encoded in mammals by the three genomic loci miR-124a-1/2/3; however, its in vivo roles in neuronal development and function remain ambiguous. In the present study, we investigated the effect of miR-124a loss on neuronal differentiation in mice and in embryonic stem (ES) cells. Since
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Human Protein Arginine Methyltransferases (PRMTs) Can Be Optimally Active Under Non-Physiological Conditions J. Biol. Chem. (IF 5.486) Pub Date : 2022-07-20 Troy L. Lowe, Steven G. Clarke
Protein arginine methylation is involved in many biological processes and can be enhanced in cancer. In mammals, these reactions are catalyzed on multiple substrates by a family of nine protein arginine methyltransferases (PRMTs). However, conditions that may regulate the activity of each enzyme and that may help us understand the physiological role of PRMTs have not been fully established. Previous