Looking back at the last two years: Coming home to JBC [Editorial]
When I was approached about putting my name in the hat for the Editor-in-Chief position at JBC, a mini-tsunami of thoughts splashed through my brain. First and foremost: Why in heck would I do that? Mulling that question over led to some clarity about why I might take this position and a growing sense of anticipated pleasure at the prospect of making some small contribution to the future vigor of a society journal that I valued in the deepest part of my core. Mind you, I had not been publishing frequently in JBC in the years prior to this introspective moment. In fact, this was presented to me as a key question by the Sear...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Lila M. Gierasch Tags: Editorial Source Type: research

MP-4 contributes to snake venom neutralization by Mucuna pruriens seeds through an indirect antibody-mediated mechanism. [Expressions of Concern]
VOLUME 291 (2016) PAGES 11373–11384The publisher of the Journal of Biological Chemistry is issuing an Expression of Concern to inform readers that credible concerns have been raised regarding the crystallography data shown in this paper. The Journal of Biological Chemistry will provide additional information as it becomes available. (Source: Journal of Biological Chemistry)
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Ashish Kumar, Chitra Gupta, Deepak T. Nair, Dinakar M. Salunke Tags: Expressions of Concern Source Type: research

A sirtuin's role in preventing senescence by protecting ribosomal DNA [Cell Biology]
Ribosomes are encoded by many copies of ribosomal DNA (rDNA) packed into the nucleolus. High rates of transcription combined with highly repetitive sequences render rDNA loci particularly vulnerable to genomic instability, a proposed underlying cause of cellular senescence. The molecular mechanisms that maintain rDNA stability have remained unclear. A new paper elucidates a sirtuin-dependent mechanism that protects rDNA loci from genomic instability and prevents cellular senescence via heterochromatin silencing mediated by the chromatin remodeler SNF2H. This finding extends our understanding of chromatin dynamics within rD...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Jean-Pierre Etchegaray, Raul Mostoslavsky Tags: Editors ' Picks Highlights Source Type: research

The epigenetic regulator SIRT7 guards against mammalian cellular senescence induced by ribosomal DNA instability [Cell Biology]
In the yeast Saccharomyces cerevisiae, genomic instability in rDNA repeat sequences is an underlying cause of cell aging and is suppressed by the chromatin-silencing factor Sir2. In humans, rDNA instability is observed in cancers and premature aging syndromes, but its underlying mechanisms and functional consequences remain unclear. Here, we uncovered a pivotal role of sirtuin 7 (SIRT7), a mammalian Sir2 homolog, in guarding against rDNA instability and show that this function of SIRT7 protects against senescence in primary human cells. We found that, mechanistically, SIRT7 is required for association of SNF2H (also called...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Silvana Paredes, Maria Angulo-Ibanez, Luisa Tasselli, Scott M. Carlson, Wei Zheng, Tie-Mei Li, Katrin F. Chua Tags: Editors ' Picks Source Type: research

Phosphorylation-mediated structural changes within the SOAR domain of stromal interaction molecule 1 enable specific activation of distinct Orai channels. [Additions and Corrections]
VOLUME 293 (2018) PAGES 3145–3155Yue Zhao should be changed to Yue Lai-Zhao, as shown in the above author line. (Source: Journal of Biological Chemistry)
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Jill L. Thompson, Yue Lai-Zhao, Peter B. Stathopulos, Alan Grossfield, Trever J. Shuttleworth Tags: Additions and Corrections Source Type: research

The Hippo pathway effector proteins YAP and TAZ have both distinct and overlapping functions in the cell [Signal Transduction]
The Hippo pathway plays an important role in regulating tissue homeostasis, and its effectors, the transcriptional co-activators Yes-associated protein (YAP) and WW domain–containing transcription regulator 1 (WWTR1 or TAZ), are responsible for mediating the vast majority of its physiological functions. Although YAP and TAZ are thought to be largely redundant and similarly regulated by Hippo signaling, they have developmental, structural, and physiological differences that suggest they may differ in their regulation and downstream functions. To better understand the functions of YAP and TAZ in the Hippo pathway, usin...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Steven W. Plouffe, Kimberly C. Lin, Jerrell L. Moore 3rd, Frederick E. Tan, Shenghong Ma, Zhen Ye, Yunjiang Qiu, Bing Ren, Kun-Liang Guan Tags: Cell Biology Source Type: research

Properly folded and functional PorB from Neisseria gonorrhoeae inhibits dendritic cell stimulation of CD4+ T cell proliferation [Immunology]
In this study, we sought to determine the gonococcal factors involved in this adaptive immune suppression. We show that suppression of the capacity of antigen-pulsed dendritic cells to induce T cell proliferation is recapitulated by administration of a high-molecular-weight fraction of conditioned medium from N. gonorrhoeae cultures, which includes outer membrane vesicles that are shed during growth of the bacteria. N. gonorrhoeae PorB is the most abundant protein in N. gonorrhoeae–derived vesicles, and treatment of dendritic cells with purified recombinant PorB inhibited the capacity of the cells to stimulate T cell...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Weiyan Zhu, Joshua Tomberg, Kayla J. Knilans, James E. Anderson, Karen P. McKinnon, Gregory D. Sempowski, Robert A. Nicholas, Joseph A. Duncan Tags: Immunology Source Type: research

Phosphoinositide binding by the PH domain in ceramide transfer protein (CERT) is inhibited by hyperphosphorylation of an adjacent serine-repeat motif [Protein Structure and Folding]
Sphingolipids such as ceramide are important constituents of cell membranes. The ceramide transfer protein (CERT) moves ceramide from the endoplasmic reticulum to the Golgi apparatus in a nonvesicular manner. Hyperphosphorylation of the serine-repeat motif (SRM) adjacent to the pleckstrin homology (PH) domain of CERT down-regulates the inter-organelle ceramide transport function of CERT. However, the mechanistic details of this down-regulation remain elusive. Using solution NMR and binding assays, we herein show that a hyperphosphorylation-mimetic CERT variant in which 10 serine/threonine residues of SRM had been replaced ...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Toshihiko Sugiki, Daichi Egawa, Keigo Kumagai, Chojiro Kojima, Toshimichi Fujiwara, Koh Takeuchi, Ichio Shimada, Kentaro Hanada, Hideo Takahashi Tags: Lipids Source Type: research

Effects of phosphatidylcholine membrane fluidity on the conformation and aggregation of N-terminally acetylated {alpha}-synuclein [Lipids]
Membrane association of α-synuclein (α-syn), a neuronal protein associated with Parkinson's disease (PD), is involved in α-syn function and pathology. Most previous studies on α-syn–membrane interactions have not used the physiologically relevant N-terminally acetylated (N-acetyl) α-syn form nor the most naturally abundant cellular lipid, i.e. phosphatidylcholine (PC). Here, we report on how PC membrane fluidity affects the conformation and aggregation propensity of N-acetyl α-syn. It is well established that upon membrane binding, α-syn adopts an α-helical structure. U...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Emma I. O'Leary, Zhiping Jiang, Marie-Paule Strub, Jennifer C. Lee Tags: Protein Structure and Folding Source Type: research

Striatin-1 is a B subunit of protein phosphatase PP2A that regulates dendritic arborization and spine development in striatal neurons [Signal Transduction]
Striatin-1, a subunit of the serine/threonine phosphatase PP2A, is preferentially expressed in neurons in the striatum. As a member of the striatin family of B subunits, striatin-1 is a core component together with PP2A of a multiprotein complex called STRIPAK, the striatin-interacting phosphatase and kinase complex. Little is known about the function of striatin-1 or the STRIPAK complex in the mammalian striatum. Here, we identify a selective role for striatin-1 in striatal neuron maturation. Using a small hairpin RNA (shRNA) knockdown approach in primary striatal neuronal cultures, we determined that reduced expression o...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Daniel Li, Veronica Musante, Wenliang Zhou, Marina R. Picciotto, Angus C. Nairn Tags: Neurobiology Source Type: research

ATP-binding cassette member B5 (ABCB5) promotes tumor cell invasiveness in human colorectal cancer [Cell Biology]
ABC member B5 (ABCB5) mediates multidrug resistance (MDR) in diverse malignancies and confers clinically relevant 5-fluorouracil resistance to CD133-expressing cancer stem cells in human colorectal cancer (CRC). Because of its recently identified roles in normal stem cell maintenance, we hypothesized that ABCB5 might also serve MDR-independent functions in CRC. Here, in a prospective clinical study of 142 CRC patients, we found that ABCB5 mRNA transcripts previously reported not to be significantly expressed in healthy peripheral blood mononuclear cells are significantly enriched in patient peripheral blood specimens compa...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Qin Guo, Tanja Grimmig, Gabriel Gonzalez, Anita Giobbie-Hurder, Gretchen Berg, Nolan Carr, Brian J. Wilson, Pallavi Banerjee, Jie Ma, Jason S. Gold, Bisweswar Nandi, Qin Huang, Ana Maria Waaga-Gasser, Christine G. Lian, George F. Murphy, Markus H. Frank, Tags: Cell Biology Source Type: research

Discovery of a new Pro-Pro endopeptidase, PPEP-2, provides mechanistic insights into the differences in substrate specificity within the PPEP family [Enzymology]
Pro-Pro endopeptidases (PPEPs) belong to a recently discovered family of proteases capable of hydrolyzing a Pro–Pro bond. The first member from the bacterial pathogen Clostridium difficile (PPEP-1) cleaves two C. difficile cell-surface proteins involved in adhesion, one of which is encoded by the gene adjacent to the ppep-1 gene. However, related PPEPs may exist in other bacteria and may shed light on substrate specificity in this enzyme family. Here, we report on the homolog of PPEP-1 in Paenibacillus alvei, which we denoted PPEP-2. We found that PPEP-2 is a secreted metalloprotease, which likewise cleaved a cell-su...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Oleg I. Klychnikov, Tatiana M. Shamorkina, Stephen D. Weeks, Hans C. van Leeuwen, Jeroen Corver, Jan W. Drijfhout, Peter A. van Veelen, Nikolai N. Sluchanko, Sergei V. Strelkov, Paul J. Hensbergen Tags: Microbiology Source Type: research

Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42 [Cell Biology]
Inflammation is a major driver of tumor progression and metastasis, although the mechanisms by which proinflammatory cytokines drive metastatic invasion are unknown. Interleukin-6 (IL-6) is a potent proinflammatory cytokine that is elevated in individuals with pancreatic cancer (PDAC), is required for PDAC progression in mice, and increases tumor cell invasion in vitro. Here, we provide insights into the mechanisms by which IL-6 activates tumor cell invasion. We found that IL-6 stimulation rapidly and robustly activates the small GTPase cell division cycle 42 (CDC42) in human PDAC cells and promotes the formation of premig...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Gina L. Razidlo, Kevin M. Burton, Mark A. McNiven Tags: Signal Transduction Source Type: research

Restoration of hydroxyindole O-methyltransferase levels in human cancer cells induces a tryptophan-metabolic switch and attenuates cancer progression [Metabolism]
5-Methoxytryptophan (5-MTP) is a tryptophan metabolite with recently discovered anti-inflammatory and tumor-suppressing activities. Its synthesis is catalyzed by a hydroxyindole O-methyltransferase (HIOMT)-like enzyme. However, the exact identity of this HIOMT in human cells remains unclear. Human HIOMT exists in several alternatively spliced isoforms, and we hypothesized that 5-MTP–producing HIOMT is a distinct isoform. Here, we show that human fibroblasts and cancer cells express the HIOMT298 isoform as contrasted with the expression of the HIOMT345 isoform in pineal cells. Sequencing analysis of the cloned isoform...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Hua-Ling Chen, Chao-Yun Yuan, Huei-Hsuan Cheng, Tzu-Ching Chang, Shau-Ku Huang, Cheng-Chin Kuo, Kenneth K. Wu Tags: Cell Biology Source Type: research

Protein kinase C{alpha} drives fibroblast activation and kidney fibrosis by stimulating autophagic flux [Molecular Bases of Disease]
Kidney fibrosis is a histological hallmark of chronic kidney disease and arises in large part through extracellular matrix deposition by activated fibroblasts. The signaling protein complex mTOR complex 2 (mTORC2) plays a critical role in fibroblast activation and kidney fibrosis. Protein kinase Cα (PKCα) is one of the major sub-pathways of mTORC2, but its role in fibroblast activation and kidney fibrosis remains to be determined. Here, we found that transforming growth factor β1 (TGFβ1) activates PKCα signaling in cultured NRK-49F cells in a time-dependent manner. Blocking PKCα signaling ...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Xian Xue, Jiafa Ren, Xiaoli Sun, Yuan Gui, Ye Feng, Bingyan Shu, Wei Wei, Qingmiao Lu, Yan Liang, Weichun He, Junwei Yang, Chunsun Dai Tags: Signal Transduction Source Type: research

The transcription factor Vezf1 represses the expression of the antiangiogenic factor Cited2 in endothelial cells [DNA and Chromosomes]
Formation of the vasculature by angiogenesis is critical for proper development, but angiogenesis also contributes to the pathogenesis of various disorders, including cancer and cardiovascular diseases. Vascular endothelial zinc finger 1 (Vezf1), is a Krüppel-like zinc finger protein that plays a vital role in vascular development. However, the mechanism by which Vezf1 regulates this process is not fully understood. Here, we show that Vezf1−/− mouse embryonic stem cells (ESC) have significantly increased expression of a stem cell factor, Cbp/p300-interacting transactivator 2 (Cited2). Compared with WT ESCs...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Lama AlAbdi, Ming He, Qianyi Yang, Allison B. Norvil, Humaira Gowher Tags: Gene Regulation Source Type: research

Impact of tobacco-specific nitrosamine-derived DNA adducts on the efficiency and fidelity of DNA replication in human cells [DNA and Chromosomes]
In this study, we investigated the effects of three stable POB DNA adducts (O2-POB-dT, O4-POB-dT, and O6-POB-dG) on the efficiency and fidelity of DNA replication in HEK293T human cells. We found that, when situated in a double-stranded plasmid, O2-POB-dT and O4-POB-dT moderately blocked DNA replication and induced exclusively T→A (∼14.9%) and T→C (∼35.2%) mutations, respectively. On the other hand, O6-POB-dG slightly impeded DNA replication, and this lesion elicited primarily the G→A transition (∼75%) together with a low frequency of the G→T transversion (∼3%). By conducting replication...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Hua Du, Jiapeng Leng, Pengcheng Wang, Lin Li, Yinsheng Wang Tags: DNA and Chromosomes Source Type: research

Structural basis for ADP-dependent glucokinase inhibition by 8-bromo-substituted adenosine nucleotide [Protein Structure and Folding]
In higher eukaryotes, several ATP-utilizing enzymes known as hexokinases activate glucose in the glycolysis pathway by phosphorylation to glucose 6-phosphate. In contrast to canonical hexokinases, which use ATP, ADP-dependent glucokinase (ADPGK) catalyzes noncanonical phosphorylation of glucose to glucose 6-phosphate using ADP as a phosphate donor. Initially discovered in Archaea, the human homolog of ADPGK was described only recently. ADPGK's involvement in modified bioenergetics of activated T cells has been postulated, and elevated ADPGK expression has been reported in various cancer tissues. However, the physiological ...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Przemysław Grudnik, Marcin M. Kamiłski, Krzysztof P. Rembacz, Katarzyna Kuśka, Mariusz Madeȷ, Jan Potempa, Macieȷ Dawidowski, Grzegorz Dubin Tags: Protein Structure and Folding Source Type: research

Decline in arylsulfatase B expression increases EGFR expression by inhibiting the protein-tyrosine phosphatase SHP2 and activating JNK in prostate cells [Signal Transduction]
Epidermal growth factor receptor (EGFR) has a crucial role in cell differentiation and proliferation and cancer, and its expression appears to be up-regulated when arylsulfatase B (ARSB or GalNAc-4-sulfatase) is reduced. ARSB removes 4-sulfate groups from the nonreducing end of dermatan sulfate and chondroitin 4-sulfate (C4S), and its decreased expression has previously been reported to inhibit the activity of the ubiquitous protein-tyrosine phosphatase, nonreceptor type 11 (SHP2 or PTPN11). However, the mechanism by which decline in ARSB leads to decline in SHP2 activity is unclear. Here, we show that SHP2 binds preferent...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Sumit Bhattacharyya, Leo Feferman, Xiaorui Han, Yilan Ouyang, Fuming Zhang, Robert J. Linhardt, Joanne K. Tobacman Tags: Glycobiology and Extracellular Matrices Source Type: research

JAK1-mediated Sirt1 phosphorylation functions as a negative feedback of the JAK1-STAT3 pathway [Signal Transduction]
The type III NAD–dependent histone deacetylase Sirt1 plays important roles in a variety of pathobiological functions through targeting either the acetylated histones or transcription factors. However, the molecular mechanisms underlying how the Sirt1 functions are regulated remain vague. Herein we identified that the Janus kinase 1 (JAK1) interacts with Sirt1 and catalyzes its phosphorylation at the tyrosine residues of 280 and 301, both of which are highly conserved and located in the histone deacetylase catalytic domain of Sirt1. IL-6 stimulation enhanced Sirt1 interaction with JAK1 and JAK1-mediated Sirt1 phosphor...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Wenhui Wang, Fei Li, Yuanming Xu, Juncheng Wei, Yana Zhang, Heeyoung Yang, Beixue Gao, Guohua Yu, Deyu Fang Tags: Signal Transduction Source Type: research

RNA-binding proteins with basic-acidic dipeptide (BAD) domains self-assemble and aggregate in Alzheimer's disease [Genomics and Proteomics]
We report here that this domain shares many of the properties of the Gln/Asn-rich LC domains in RBPs that also aggregate in neurodegenerative disease. These properties included self-assembly into oligomers and localization to nuclear granules. Co-immunoprecipitations of recombinant U1-70K and deletions lacking the LC domain(s) followed by quantitative proteomic analyses were used to resolve functional classes of U1-70K-interacting proteins that depend on the BAD domain for their interaction. Within this interaction network, we identified a class of RBPs with BAD domains nearly identical to that found in U1-70K. Two members...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Isaac Bishof, Eric B. Dammer, Duc M. Duong, Sean R. Kundinger, Marla Gearing, James J. Lah, Allan I. Levey, Nicholas T. Seyfried Tags: Molecular Bases of Disease Source Type: research

Protein kinase A-mediated phosphorylation of serine 357 of the mouse prostacyclin receptor regulates its coupling to Gs-, to Gi-, and to Gq-coupled effector signaling. [Additions and Corrections]
VOLUME 276 (2001) PAGES 33596–33607PAGE 33605:During a recent review of this article, the authors realized that there may have been unspecified reordering of lanes in Fig. 11B and possible duplication of lanes 2 between Fig. 11, B and C. As the original data were no longer available, replicate data are provided. This correction does not affect the results or conclusions of this work. The authors wish to apologize for any inconvenience this error may have caused.jbc;293/28/11046/FU1F1FU1 (Source: Journal of Biological Chemistry)
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Orlaith A. Lawler, Sinead M. Miggin, B. Therese Kinsella Tags: Additions and Corrections Source Type: research

Lysophospholipids induce innate immune transdifferentiation of endothelial cells, resulting in prolonged endothelial activation [Gene Regulation]
In conclusion, lysophospholipids such as LPC and LPI induce innate immune cell transdifferentiation in HAECs. The concept of prolonged endothelial activation, discovered here, is relevant for designing new strategies for managing cardiovascular diseases. (Source: Journal of Biological Chemistry)
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Xinyuan Li, Luqiao Wang, Pu Fang, Yu Sun, Xiaohua Jiang, Hong Wang, Xiao-Feng Yang Tags: RNA Source Type: research

Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K+ currents in cardiomyocytes and prolongs cardiac action potential duration [Cell Biology]
In this study, we report that activation of SMO with SHH (Sonic Hedgehog) or a small agonist, purmorphamine, rapidly causes a prolongation of the action potential duration that is sensitive to a SMO inhibitor. In contrast, neither of the SMO agonists prolonged the action potential in cardiomyocytes from transgenic GiCT/TTA mice, in which Gi signaling is impaired, suggesting that the effect of SMO is mediated by Gi proteins. Investigation of the mechanism underlying the change in action potential kinetics revealed that activation of SMO selectively reduces outward voltage-gated K+ repolarizing (Kv) currents in isolated card...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Lan Cheng, Moza Al-Owais, Manuel L. Covarrubias, Walter J. Koch, David. R. Manning, Chris Peers, Natalia A. Riobo-Del Galdo Tags: Signal Transduction Source Type: research

Select {alpha}-arrestins control cell-surface abundance of the mammalian Kir2.1 potassium channel in a yeast model [Membrane Biology]
Protein composition at the plasma membrane is tightly regulated, with rapid protein internalization and selective targeting to the cell surface occurring in response to environmental changes. For example, ion channels are dynamically relocalized to or from the plasma membrane in response to physiological alterations, allowing cells and organisms to maintain osmotic and salt homeostasis. To identify additional factors that regulate the selective trafficking of a specific ion channel, we used a yeast model for a mammalian potassium channel, the K+ inward rectifying channel Kir2.1. Kir2.1 maintains potassium homeostasis in he...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Natalie A. Hager, Collin J. Krasowski, Timothy D. Mackie, Alexander R. Kolb, Patrick G. Needham, Andrew A. Augustine, Alison Dempsey, Christopher Szent-Gyorgyi, Marcel P. Bruchez, Daniel J. Bain, Adam V. Kwiatkowski, Allyson F. O'Donnell, Jeffrey L. Brods Tags: Cell Biology Source Type: research

The stimulatory G protein Gs{alpha} is required in melanocortin 4 receptor-expressing cells for normal energy balance, thermogenesis, and glucose metabolism [Signal Transduction]
In this study, we examined the effects of Gsα in MC4R-expressing cells on metabolic regulation. Mice with homozygous Gsα deficiency in MC4R-expressing cells (MC4RGsKO) developed significant obesity with increased food intake and decreased energy expenditure, along with impaired insulin sensitivity and cold-induced thermogenesis. Moreover, the ability of the MC4R agonist melanotan-II (MTII) to stimulate energy expenditure and to inhibit food intake was impaired in MC4RGsKO mice. MTII failed to stimulate the secretion of the anorexigenic hormone peptide YY (PYY) from enteroendocrine L cells, a physiological respo...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Brandon Podyma, Hui Sun, Eric A. Wilson, Bradley Carlson, Ethan Pritikin, Oksana Gavrilova, Lee S. Weinstein, Min Chen Tags: Metabolism Source Type: research

Structural basis for selective inhibition of human PKG I{alpha} by the balanol-like compound N46 [Protein Structure and Folding]
In conclusion, our results explain the structural basis for N46-mediated selective inhibition of human PKG Iα and provide a starting point for structure-guided design of selective PKG Iα inhibitors. (Source: Journal of Biological Chemistry)
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Liying Qin, Banumathi Sankaran, Sahar Aminzai, Darren E. Casteel, Choel Kim Tags: Signal Transduction Source Type: research

Interleukin-6-mediated trans-signaling inhibits transforming growth factor-{beta} signaling in trabecular meshwork cells [Molecular Bases of Disease]
Glaucoma is one of the major causes of blindness, and transforming growth factor-β2 (TGF-β2) has been found to be elevated in the aqueous humor of eyes with primary open-angle glaucoma (POAG). TGF-β2 in aqueous humor causes the glaucoma-related fibrosis of human trabecular meshwork (HTM), suggesting an important role of TGF-β in POAG pathogenesis. Here, we sought to elucidate the effects of IL-6 trans-signaling on TGF-β signaling in HTM cells. Using a multiplex immunoassay, POAG patients decreased IL-6 levels and increased soluble IL-6 receptor (sIL-6R) levels compared with the controls. In in vitr...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Miyuki Inoue-Mochita, Toshihiro Inoue, Sachi Kojima, Akiko Futakuchi, Tomokazu Fujimoto, Saori Sato-Ohira, Utako Tsutsumi, Hidenobu Tanihara Tags: Cell Biology Source Type: research

A heterodimer formed by bone morphogenetic protein 9 (BMP9) and BMP10 provides most BMP biological activity in plasma [Molecular Bases of Disease]
Bone morphogenetic protein 9 (BMP9) and BMP10 are the two high-affinity ligands for the endothelial receptor activin receptor-like kinase 1 (ALK1) and are key regulators of vascular remodeling. They are both present in the blood, but their respective biological activities are still a matter of debate. The aim of the present work was to characterize their circulating forms to better understand how their activities are regulated in vivo. First, by cotransfecting BMP9 and BMP10, we found that both can form a disulfide-bonded heterodimer in vitro and that this heterodimer is functional on endothelial cells via ALK1. Next, we d...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Emmanuelle Tillet, Marie Ouarne, Agnes Desroches–Castan, Christine Mallet, Mariela Subileau, Robin Didier, Anna Lioutsko, Guillaume Belthier, Jean–Jacques Feige, Sabine Bailly Tags: Cell Biology Source Type: research

Sequence diversity of tubulin isotypes in regulation of the mitochondrial voltage-dependent anion channel [Molecular Biophysics]
The microtubule protein tubulin is a heterodimer comprising α/β subunits, in which each subunit features multiple isotypes in vertebrates. For example, seven α-tubulin and eight β-tubulin isotypes in the human tubulin gene family vary mostly in the length and primary sequence of the disordered anionic carboxyl-terminal tails (CTTs). The biological reason for such sequence diversity remains a topic of vigorous enquiry. Here, we demonstrate that it may be a key feature of tubulin's role in regulation of the permeability of the mitochondrial outer membrane voltage-dependent anion channel (VDAC). Using re...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Tatiana K. Rostovtseva, Philip A. Gurnev, David P. Hoogerheide, Amandine Rovini, Minhajuddin Sirajuddin, Sergey M. Bezrukov Tags: Molecular Biophysics Source Type: research

Arginine methylation of translocated in liposarcoma (TLS) inhibits its binding to long noncoding RNA, abrogating TLS-mediated repression of CBP/p300 activity [RNA]
Translocated in liposarcoma (TLS) is an RNA-binding protein and a transcription-regulatory sensor of DNA damage. TLS binds promoter-associated noncoding RNA (pncRNA) and inhibits histone acetyltransferase (HAT) activity of CREB-binding protein (CBP)/E1A-binding protein P300 (p300) on the cyclin D1 (CCND1) gene. Although post-translational modifications of TLS, such as arginine methylation, are known to regulate TLS's nucleocytoplasmic shuttling and assembly in stress granules, its interactions with RNAs remain poorly characterized. Herein, using various biochemical assays, we confirmed the earlier observations that TLS is ...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Wei Cui, Ryoma Yoneda, Naomi Ueda, Riki Kurokawa Tags: Gene Regulation Source Type: research

The C-terminal region of the yeast monocarboxylate transporter Jen1 acts as a glucose signal-responding degron recognized by the {alpha}-arrestin Rod1 [Cell Biology]
In response to changes in nutrient conditions, cells rearrange the composition of plasma membrane (PM) transporters to optimize their metabolic flux. Not only transcriptional gene regulation, but also inactivation of specific transporters is important for fast rearrangement of the PM. In eukaryotic cells, endocytosis plays a role in transporter inactivation, which is triggered by ubiquitination of these transporters. The Nedd4 family E3 ubiquitin ligase is responsible for ubiquitination of the PM transporters and requires that a series of α-arrestin proteins are targeted to these transporters. The mechanism by which ...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Shoki Fujita, Daichi Sato, Hirokazu Kasai, Masataka Ohashi, Shintaro Tsukue, Yutaro Takekoshi, Katsuya Gomi, Takahiro Shintani Tags: Protein Synthesis and Degradation Source Type: research

CHCA-1 is a copper-regulated CTR1 homolog required for normal development, copper accumulation, and copper-sensing behavior in Caenorhabditis elegans [Cell Biology]
Copper plays key roles in catalytic and regulatory biochemical reactions essential for normal growth, development, and health. Dietary copper deficiencies or mutations in copper homeostasis genes can lead to abnormal musculoskeletal development, cognitive disorders, and poor growth. In yeast and mammals, copper is acquired through the activities of the CTR1 family of high-affinity copper transporters. However, the mechanisms of systemic responses to dietary or tissue-specific copper deficiency remain unclear. Here, taking advantage of the animal model Caenorhabditis elegans for studying whole-body copper homeostasis, we in...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Sai Yuan, Anuj Kumar Sharma, Alexandria Richart, Jaekwon Lee, Byung-Eun Kim Tags: Metabolism Source Type: research

Structure-based stabilization of insulin as a therapeutic protein assembly via enhanced aromatic-aromatic interactions [Molecular Biophysics]
Key contributions to protein structure and stability are provided by weakly polar interactions, which arise from asymmetric electronic distributions within amino acids and peptide bonds. Of particular interest are aromatic side chains whose directional π-systems commonly stabilize protein interiors and interfaces. Here, we consider aromatic–aromatic interactions within a model protein assembly: the dimer interface of insulin. Semi-classical simulations of aromatic–aromatic interactions at this interface suggested that substitution of residue TyrB26 by Trp would preserve native structure while enhancing dimer...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Nischay K. Rege, Nalinda P. Wickramasinghe, Alisar N. Tustan, Nelson F. B. Phillips, Vivien C. Yee, Faramarz Ismail-Beigi, Michael A. Weiss Tags: Protein Structure and Folding Source Type: research

Inhibition of protein arginine methyltransferase 5 enhances hepatic mitochondrial biogenesis [Metabolism]
Protein arginine methyltransferase 5 (PRMT5) regulates gene expression either transcriptionally by symmetric dimethylation of arginine residues on histones H4R3, H3R8, and H2AR3 or at the posttranslational level by methylation of nonhistone target proteins. Although emerging evidence suggests that PRMT5 functions as an oncogene, its role in metabolic diseases is not well-defined. We investigated the role of PRMT5 in promoting high-fat–induced hepatic steatosis. A high-fat diet up-regulated PRMT5 levels in the liver but not in other metabolically relevant tissues such as skeletal muscle or white and brown adipose tiss...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Lei Huang, Jehnan Liu, Xiao-Ou Zhang, Katelyn Sibley, Sonia M. Najjar, Mary M. Lee, Qiong Wu Tags: Gene Regulation Source Type: research

Ethanolamine ameliorates mitochondrial dysfunction in cardiolipin-deficient yeast cells [Bioenergetics]
Cardiolipin (CL) is a signature phospholipid of the mitochondria required for the formation of mitochondrial respiratory chain (MRC) supercomplexes. The destabilization of MRC supercomplexes is the proximal cause of the pathology associated with the depletion of CL in patients with Barth syndrome. Thus, promoting supercomplex formation could ameliorate mitochondrial dysfunction associated with CL depletion. However, to date, physiologically relevant small-molecule regulators of supercomplex formation have not been identified. Here, we report that ethanolamine (Etn) supplementation rescues the MRC defects by promoting super...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Writoban Basu Ball, Charli D. Baker, John K. Neff, Gabriel L. Apfel, Kim A. Lagerborg, Gašper Žun, Uroš Petrovič, Mohit Jain, Vishal M. Gohil Tags: Metabolism Source Type: research

Oxidative decarboxylation of pyruvate by 1-deoxy-d-xyulose 5-phosphate synthase, a central metabolic enzyme in bacteria [Molecular Biophysics]
The underexploited antibacterial target 1-deoxy-d-xyluose 5-phosphate (DXP) synthase catalyzes the thiamin diphosphate (ThDP)-dependent formation of DXP from pyruvate and d-glyceraldehyde 3-phosphate (d-GAP). DXP is an essential intermediate in the biosynthesis of ThDP, pyridoxal phosphate, and isoprenoids in many pathogenic bacteria. DXP synthase catalyzes a distinct mechanism in ThDP decarboxylative enzymology in which the first enzyme-bound pre-decarboxylation intermediate, C2α-lactyl-ThDP (LThDP), is stabilized by DXP synthase in the absence of d-GAP, and d-GAP then induces efficient LThDP decarboxylation. Despit...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Alicia A. DeColli, Natalia S. Nemeria, Ananya Majumdar, Gary J. Gerfen, Frank Jordan, Caren L. Freel Meyers Tags: Enzymology Source Type: research

Redistribution of SERCA calcium pump conformers during intracellular calcium signaling [Molecular Biophysics]
The conformational changes of a calcium transport ATPase were investigated with molecular dynamics (MD) simulations as well as fluorescence resonance energy transfer (FRET) measurements to determine the significance of a discrete structural element for regulation of the conformational dynamics of the transport cycle. Previous MD simulations indicated that a loop in the cytosolic domain of the SERCA calcium transporter facilitates an open-to-closed structural transition. To investigate the significance of this structural element, we performed additional MD simulations and new biophysical measurements of SERCA structure and ...
Source: Journal of Biological Chemistry - July 13, 2018 Category: Chemistry Authors: Olga N. Raguimova, Nikolai Smolin, Elisa Bovo, Siddharth Bhayani, Joseph M. Autry, Aleksey V. Zima, Seth L. Robia Tags: Membrane Biology Source Type: research

The sulfation code for propagation of neurodegeneration [Protein Structure and Folding]
Prion-like propagation of protein aggregates is thought to be an essential feature in many neurodegenerative diseases, but the mechanisms underlying transcellular transfer of protein aggregates remain unclear. Stopschinski et al. now demonstrate that the cellular uptake of tau, Aβ, and α-synuclein aggregates mediated by heparan sulfate proteoglycans (HSPGs) varies with distinct glycosaminoglycan chain length and sulfation patterns. The results help us to understand how different protein aggregates propagate, leading to distinct neurodegenerative pathologies. (Source: Journal of Biological Chemistry)
Source: Journal of Biological Chemistry - July 6, 2018 Category: Chemistry Authors: Masahito Yamada, Tsuyoshi Hamaguchi Tags: Editors ' Picks Highlights Source Type: research

Specific glycosaminoglycan chain length and sulfation patterns are required for cell uptake of tau versus {alpha}-synuclein and {beta}-amyloid aggregates [Neurobiology]
Transcellular propagation of protein aggregate “seeds” has been proposed to mediate the progression of neurodegenerative diseases in tauopathies and α-synucleinopathies. We previously reported that tau and α-synuclein aggregates bind heparan sulfate proteoglycans (HSPGs) on the cell surface, promoting cellular uptake and intracellular seeding. However, the specificity and binding mode of these protein aggregates to HSPGs remain unknown. Here, we measured direct interaction with modified heparins to determine the size and sulfation requirements for tau, α-synuclein, and β-amyloid (Aβ)...
Source: Journal of Biological Chemistry - July 6, 2018 Category: Chemistry Authors: Barbara E. Stopschinski, Brandon B. Holmes, Gregory M. Miller, Victor A. Manon, Jaime Vaquer-Alicea, William L. Prueitt, Linda C. Hsieh-Wilson, Marc I. Diamond Tags: Editors ' Picks Source Type: research

Antagonism between the dynein and Ndc80 complexes at kinetochores controls the stability of kinetochore-microtubule attachments during mitosis. [Additions and Corrections]
VOLUME 293 (2018) PAGES 5755–5765PAGE 5757:Fig. 2A was inadvertently duplicated in Fig. 1D during figure assembly. This error has now been corrected and does not affect the results or conclusions of this work.jbc;293/27/10825/FU1F1FU1 (Source: Journal of Biological Chemistry)
Source: Journal of Biological Chemistry - July 6, 2018 Category: Chemistry Authors: Mohammed A. Amin, Richard J. McKenney, Dileep Varma Tags: Additions and Corrections Source Type: research

O-GlcNAc transferase missense mutations linked to X-linked intellectual disability deregulate genes involved in cell fate determination and signaling [Molecular Bases of Disease]
It is estimated that ∼1% of the world's population has intellectual disability, with males affected more often than females. OGT is an X-linked gene encoding for the enzyme O-GlcNAc transferase (OGT), which carries out the reversible addition of N-acetylglucosamine (GlcNAc) to Ser/Thr residues of its intracellular substrates. Three missense mutations in the tetratricopeptide (TPR) repeats of OGT have recently been reported to cause X-linked intellectual disability (XLID). Here, we report the discovery of two additional novel missense mutations (c.775 G>A, p.A259T, and c.1016 A>G, p.E339G) in the TPR domain of OGT...
Source: Journal of Biological Chemistry - July 6, 2018 Category: Chemistry Authors: Nithya Selvan, Stephan George, Fatema J. Serajee, Marie Shaw, Lynne Hobson, Vera Kalscheuer, Nripesh Prasad, Shawn E. Levy, Juliet Taylor, Salim Aftimos, Charles E. Schwartz, Ahm M. Huq, Jozef Gecz, Lance Wells Tags: Glycobiology and Extracellular Matrices Source Type: research

The disorderly conduct of Hsc70 and its interaction with the Alzheimer's-related Tau protein [Molecular Biophysics]
Hsp70 chaperones bind to various protein substrates for folding, trafficking, and degradation. Considerable structural information is available about how prokaryotic Hsp70 (DnaK) binds substrates, but less is known about mammalian Hsp70s, of which there are 13 isoforms encoded in the human genome. Here, we report the interaction between the human Hsp70 isoform heat shock cognate 71-kDa protein (Hsc70 or HSPA8) and peptides derived from the microtubule-associated protein Tau, which is linked to Alzheimer's disease. For structural studies, we used an Hsc70 construct (called BETA) comprising the substrate-binding domain but l...
Source: Journal of Biological Chemistry - July 6, 2018 Category: Chemistry Authors: Isabelle R. Taylor, Atta Ahmad, Taia Wu, Bryce A. Nordhues, Anup Bhullar, Jason E. Gestwicki, Erik R. P. Zuiderweg Tags: Protein Structure and Folding Source Type: research

Altered sterol metabolism in budding yeast affects mitochondrial iron-sulfur (Fe-S) cluster synthesis [Metabolism]
Ergosterol synthesis is essential for cellular growth and viability of the budding yeast Saccharomyces cerevisiae, and intracellular sterol distribution and homeostasis are therefore highly regulated in this species. Erg25 is an iron-containing C4-methyl sterol oxidase that contributes to the conversion of 4,4-dimethylzymosterol to zymosterol, a precursor of ergosterol. The ERG29 gene encodes an endoplasmic reticulum (ER)-associated protein, and here we identified a role for Erg29 in the methyl sterol oxidase step of ergosterol synthesis. ERG29 deletion resulted in lethality in respiring cells, but respiration-incompetent ...
Source: Journal of Biological Chemistry - July 6, 2018 Category: Chemistry Authors: Diane M. Ward, Opal S. Chen, Liangtao Li, Jerry Kaplan, Shah Alam Bhuiyan, Selvamuthu K. Natarajan, Martin Bard, James E. Cox Tags: Cell Biology Source Type: research

A bipartite periplasmic receptor-diguanylate cyclase pair (XAC2383-XAC2382) in the bacterium Xanthomonas citri [Protein Structure and Folding]
The second messenger cyclic diguanylate monophosphate (c-di-GMP) is a central regulator of bacterial lifestyle, controlling several behaviors, including the switch between sessile and motile states. The c-di-GMP levels are controlled by the interplay between diguanylate cyclases (DGCs) and phosphodiesterases, which synthesize and hydrolyze this second messenger, respectively. These enzymes often contain additional domains that regulate activity via binding of small molecules, covalent modification, or protein–protein interactions. A major challenge remains to understand how DGC activity is regulated by these addition...
Source: Journal of Biological Chemistry - July 6, 2018 Category: Chemistry Authors: Raphael D. Teixeira, Cristiane R. Guzzo, Santiago Justo Arevalo, Maxuel O. Andrade, Josielle Abrahao, Robson F. de Souza, Chuck S. Farah Tags: Microbiology Source Type: research

Pore-lining residues of MEC-4 and MEC-10 channel subunits tune the Caenorhabditis elegans degenerin channel's response to shear stress [Molecular Biophysics]
The Caenorhabditis elegans MEC-4/MEC-10 channel mediates the worm's response to gentle body touch and is activated by laminar shear stress (LSS) when expressed in Xenopus oocytes. Substitutions at multiple sites within the second transmembrane domain (TM2) of MEC-4 or MEC-10 abolish the gentle touch response in worms, but the roles of these residues in mechanosensing are unclear. The present study therefore examined the role of specific MEC-4 and MEC-10 TM2 residues in the channel's response to LSS. We found that introducing mutations within the TM2 of MEC-4 or MEC-10 not only altered channel activity, but also affected th...
Source: Journal of Biological Chemistry - July 6, 2018 Category: Chemistry Authors: Shujie Shi, Stephanie M. Mutchler, Brandon M. Blobner, Ossama B. Kashlan, Thomas R. Kleyman Tags: Membrane Biology Source Type: research

Genetic code expansion and live cell imaging reveal that Thr-308 phosphorylation is irreplaceable and sufficient for Akt1 activity [Signal Transduction]
The proto-oncogene Akt/protein kinase B (PKB) is a pivotal signal transducer for growth and survival. Growth factor stimulation leads to Akt phosphorylation at two regulatory sites (Thr-308 and Ser-473), acutely activating Akt signaling. Delineating the exact role of each regulatory site is, however, technically challenging and has remained elusive. Here, we used genetic code expansion to produce site-specifically phosphorylated Akt1 to dissect the contribution of each regulatory site to Akt1 activity. We achieved recombinant production of full-length Akt1 containing site-specific pThr and pSer residues for the first time....
Source: Journal of Biological Chemistry - July 6, 2018 Category: Chemistry Authors: Nileeka Balasuriya, Maya T. Kunkel, Xuguang Liu, Kyle K. Biggar, Shawn S.-C. Li, Alexandra C. Newton, Patrick O'Donoghue Tags: Enzymology Source Type: research

Glycogen synthase kinase-3 (GSK-3) activity regulates mRNA methylation in mouse embryonic stem cells [Gene Regulation]
Glycogen synthase kinase-3 (GSK-3) activity regulates multiple signal transduction pathways and is also a key component of the network responsible for maintaining stem cell pluripotency. Genetic deletion of Gsk-3α and Gsk-3β or inhibition of GSK-3 activity via small molecules promotes stem cell pluripotency, yet the mechanism underlying the role for GSK-3 in this process remains ambiguous. Another cellular process that has been shown to affect stem cell pluripotency is mRNA methylation (m6A). Here, we describe an intersection between these components, the regulation of m6A by GSK-3. We find that protein levels f...
Source: Journal of Biological Chemistry - July 6, 2018 Category: Chemistry Authors: Kelsie J. Faulds, Jennifer N. Egelston, Laura J. Sedivy, Matthew K. Mitchell, Sanjana Garimella, Hanna Kozlowski, Angelo D'Alessandro, Kirk C. Hansen, Jeremy L. Balsbaugh, Christopher J. Phiel Tags: Signal Transduction Source Type: research

MgATP hydrolysis destabilizes the interaction between subunit H and yeast V1-ATPase, highlighting H's role in V-ATPase regulation by reversible disassembly [Bioenergetics]
Vacuolar H+-ATPases (V-ATPases; V1Vo-ATPases) are rotary-motor proton pumps that acidify intracellular compartments and, in some tissues, the extracellular space. V-ATPase is regulated by reversible disassembly into autoinhibited V1-ATPase and Vo proton channel sectors. An important player in V-ATPase regulation is subunit H, which binds at the interface of V1 and Vo. H is required for MgATPase activity in holo-V-ATPase but also for stabilizing the MgADP-inhibited state in membrane-detached V1. However, how H fulfills these two functions is poorly understood. To characterize the H–V1 interaction and its role in rever...
Source: Journal of Biological Chemistry - July 6, 2018 Category: Chemistry Authors: Stuti Sharma, Rebecca A. Oot, Stephan Wilkens Tags: Bioenergetics Source Type: research

A human-specific, truncated {alpha}7 nicotinic receptor subunit assembles with full-length {alpha}7 and forms functional receptors with different stoichiometries [Signal Transduction]
The cholinergic α7 nicotinic receptor gene, CHRNA7, encodes a subunit that forms the homopentameric α7 receptor, involved in learning and memory. In humans, exons 5–10 in CHRNA7 are duplicated and fused to the FAM7A genetic element, giving rise to the hybrid gene CHRFAM7A. Its product, dupα7, is a truncated subunit lacking part of the N-terminal extracellular ligand-binding domain and is associated with neurological disorders, including schizophrenia, and immunomodulation. We combined dupα7 expression on mammalian cells with patch clamp recordings to understand its functional role. Transfected...
Source: Journal of Biological Chemistry - July 6, 2018 Category: Chemistry Authors: Matias Lasala, Jeremias Corradi, Ariana Bruzzone, Maria del Carmen Esandi, Cecilia Bouzat Tags: Molecular Biophysics Source Type: research