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Allosteric disulfide

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https://www.readbyqxmd.com/read/29661938/dual-functionality-of-%C3%AE-tryptase-protomers-as-both-proteases-and-cofactors-in-the-active-tetramer
#1
Henry R Maun, Peter S Liu, Yvonne Franke, Charles Eigenbrot, William F Forrest, Lawrence B Schwartz, Robert A Lazarus
Human β-tryptase, a tetrameric trypsin-like serine protease, is an important mediator of the allergic inflammatory responses in asthma. During acute hypersensitivity reactions, mast cells degranulate, releasing active tetramer as a complex with proteoglycans. Extensive efforts have focused on developing therapeutic β-tryptase inhibitors, but its unique activation mechanism is less well explored. Tryptase is active only after proteolytic removal of the pro-domain followed by tetramer formation via two distinct symmetry-related interfaces...
April 16, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29570977/cystamine-and-disulfiram-inhibit-human-transglutaminase-2-via-an-oxidative-mechanism
#2
Brad Palanski, Chaitan Khosla
The catalytic activity of transglutaminase 2 (TG2), a ubiquitously expressed mammalian enzyme, is regulated by multiple post-translational mechanisms. Because elevated activity of TG2 in the extracellular matrix is associated with organ-specific diseases such as celiac disease and renal fibrosis, there is growing therapeutic interest in inhibitors of this enzyme. Cystamine, a symmetric disulfide compound, is one of the earliest reported TG2 inhibitors. Despite its widespread use as a tool compound to block TG2 activity in vitro and in vivo, its mechanism of action has remained unclear...
March 23, 2018: Biochemistry
https://www.readbyqxmd.com/read/29540480/structural-basis-for-the-catalytic-mechanism-and-%C3%AE-ketoglutarate-cooperativity-of-glutamate-dehydrogenase
#3
Prem Prakash, Narayan S Punekar, Prasenjit Bhaumik
Glutamate dehydrogenase (GDH) is a key enzyme connecting carbon and nitrogen metabolism in all living organisms. Despite extensive studies on GDHs from both prokaryotic and eukaryotic organisms in the last 40 years, the structural basis of the catalytic features of this enzyme remains incomplete. This study reports the structural basis of the GDH catalytic mechanism and allosteric behavior. We determined the first high-resolution crystal structures of glutamate dehydrogenase from the fungus Aspergillus niger (AnGDH), a unique NADP+ -dependent allosteric enzyme that is forward inhibited by the formation of mixed disulfide...
March 14, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29515832/identification-of-allosteric-disulfides-from-labile-bonds-in-x-ray-structures
#4
Aster E Pijning, Joyce Chiu, Reichelle X Yeo, Jason W H Wong, Philip J Hogg
Protein disulfide bonds link pairs of cysteine sulfur atoms and are either structural or functional motifs. The allosteric disulfides control the function of the protein in which they reside when cleaved or formed. Here, we identify potential allosteric disulfides in all Protein Data Bank X-ray structures from bonds that are present in some molecules of a protein crystal but absent in others, or present in some structures of a protein but absent in others. We reasoned that the labile nature of these disulfides signifies a propensity for cleavage and so possible allosteric regulation of the protein in which the bond resides...
February 2018: Royal Society Open Science
https://www.readbyqxmd.com/read/29507883/autoregulation-of-von-willebrand-factor-function-by-a-disulfide-bond-switch
#5
Diego Butera, Freda Passam, Lining Ju, Kristina M Cook, Heng Woon, Camilo Aponte-Santamaría, Elizabeth Gardiner, Amanda K Davis, Deirdre A Murphy, Agnieszka Bronowska, Brenda M Luken, Carsten Baldauf, Shaun Jackson, Robert Andrews, Frauke Gräter, Philip J Hogg
Force-dependent binding of platelet glycoprotein Ib (GPIb) receptors to plasma von Willebrand factor (VWF) plays a key role in hemostasis and thrombosis. Previous studies have suggested that VWF activation requires force-induced exposure of the GPIb binding site in the A1 domain that is autoinhibited by the neighboring A2 domain. However, the biochemical basis of this "mechanopresentation" remains elusive. From a combination of protein chemical, biophysical, and functional studies, we find that the autoinhibition is controlled by the redox state of an unusual disulfide bond near the carboxyl terminus of the A2 domain that links adjacent cysteine residues to form an eight-membered ring...
February 2018: Science Advances
https://www.readbyqxmd.com/read/29475957/an-isomerase-completes-the-circuit-for-a-redox-switch
#6
Gustavo Salinas
The activity of human transglutaminase 2 (TG2), which forms protein cross-links between glutamine and lysine residues, is controlled by an allosteric disulfide bond. However, the mechanism by which this bond is formed, like many systems regulated by oxidative cysteine modifications, was not clear. A new study from Khosla and colleagues shows that TG2 is oxidatively inactivated by the protein disulfide isomerase ERp57, providing the first example of a defined and reversible protein-controlled redox switch and pointing to new strategies to inhibit undesirable TG2 activity in pathological states...
February 23, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29470989/redox-exchange-of-the-disulfides-of-human-two-domain-cd4-regulates-the-conformational-dynamics-of-each-domain-providing-insight-into-its-mechanisms-of-control
#7
Gavin R Owen, Doris Le, Stoyan Stoychev, Nichole M Cerutti, Maria Papathanasopoulos
CD4, a membrane glycoprotein expressed by specific leukocytes, plays a vital role in the human immune response and acts as a primary receptor for HIV entry. Of its four ecto-domains (D1-D4), D1, D2, and D4 each contain a distinctive disulfide bond. Whereas the disulfides of D1 and D4 are more traditional in nature, providing structural functions, that of D2 is referred to as an "allosteric" disulfide due to its high dihedral strain energy and relative ease of reduction that is thought to regulate CD4 structure and function by shuffling its redox state...
February 19, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29440720/structure-of-prothrombin-in-the-closed-form-reveals-new-details-on-the-mechanism-of-activation
#8
Mathivanan Chinnaraj, Zhiwei Chen, Leslie A Pelc, Zachary Grese, Dominika Bystranowska, Enrico Di Cera, Nicola Pozzi
The clotting factor prothrombin exists in equilibrium between closed and open conformations, but the physiological role of these forms remains unclear. As for other allosteric proteins, elucidation of the linkage between molecular transitions and function is facilitated by reagents stabilized in each of the alternative conformations. The open form of prothrombin has been characterized structurally, but little is known about the architecture of the closed form that predominates in solution under physiological conditions...
February 13, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29377794/hepatitis-b-virus-core-protein-allosteric-modulators-can-distort-and-disrupt-intact-capsids
#9
Christopher John Schlicksup, Joseph Che-Yen Wang, Samson Francis, Balasubramanian Venkatakrishnan, William W Turner, Michael VanNieuwenhze, Adam Zlotnick
Defining mechanisms of direct-acting antivirals facilitates drug development and our understanding of virus function. Heteroaryldihydropyrimidines (HAPs) inappropriately activate assembly of hepatitis B virus (HBV) core protein (Cp), suppressing formation of virions. We examined a fluorophore-labeled HAP, HAP-TAMRA. HAP-TAMRA induced Cp assembly and also bound pre-assembled capsids. Kinetic and spectroscopic studies imply that HAP-binding sites are usually not available but are bound cooperatively. Using cryo-EM, we observed that HAP-TAMRA asymmetrically deformed capsids, creating a heterogeneous array of sharp angles, flat regions, and outright breaks...
January 29, 2018: ELife
https://www.readbyqxmd.com/read/29305423/endoplasmic-reticulum-resident-protein-57-erp57-oxidatively-inactivates-human-transglutaminase-2
#10
Michael C Yi, Arek V Melkonian, James A Ousey, Chaitan Khosla
Transglutaminase 2 (TG2) is a ubiquitously expressed, intracellular as well as extracellular protein with multiple modes of post-translational regulation, including an allosteric disulfide bond between Cys-370-Cys-371 that renders the enzyme inactive in the extracellular matrix. Although recent studies have established that extracellular TG2 is switched "on" by the redox cofactor protein thioredoxin-1 (TRX), it is unclear how TG2 is switched "off." Here, we demonstrate that TG2 oxidation by small-molecule biological oxidants, including glutathione, cystine, and hydrogen peroxide, is unlikely to be the inactivation mechanism...
February 23, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29298893/allosteric-control-of-human-cystathionine-%C3%AE-synthase-activity-by-a-redox-active-disulfide-bond
#11
Weining Niu, Jun Wang, Jing Qian, Mengying Wang, Ping Wu, Fei Chen, Shasha Yan
Cystathionine β-synthase (CBS) is the central enzyme in the trans-sulfuration pathway that converts homocysteine to cysteine. It is also one of the three major enzymes involved in the biogenesis of H2 S. CBS is a complex protein with a modular three-domain architecture, the central domain of which contains a272 C XX C275 motif whose function has yet to be determined. In the present study, we demonstrated that the C XX C motif exists in oxidized and reduced states in the recombinant enzyme by mass spectroscopic analysis and a thiol labeling assay...
February 16, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29296021/homocysteine-directly-interacts-and-activates-the-angiotensin-ii-type-i-receptor-to-aggravate-vascular-injury
#12
Tuoyi Li, Bing Yu, Zhixin Liu, Jingyuan Li, Mingliang Ma, Yingbao Wang, Mingjiang Zhu, Huiyong Yin, Xiaofeng Wang, Yi Fu, Fang Yu, Xian Wang, Xiaohong Fang, Jinpeng Sun, Wei Kong
Hyperhomocysteinemia (HHcy) is a risk factor for various cardiovascular diseases. However, the mechanism underlying HHcy-aggravated vascular injury remains unclear. Here we show that the aggravation of abdominal aortic aneurysm by HHcy is abolished in mice with genetic deletion of the angiotensin II type 1 (AT1) receptor and in mice treated with an AT1 blocker. We find that homocysteine directly activates AT1 receptor signalling. Homocysteine displaces angiotensin II and limits its binding to AT1 receptor. Bioluminescence resonance energy transfer analysis reveals distinct conformational changes of AT1 receptor upon binding to angiotensin II and homocysteine...
January 2, 2018: Nature Communications
https://www.readbyqxmd.com/read/29222417/insulin-in-motion-the-a6-a11-disulfide-bond-allosterically-modulates-structural-transitions-required-for-insulin-activity
#13
Bianca van Lierop, Shee Chee Ong, Alessia Belgi, Carlie Delaine, Sofianos Andrikopoulos, Naomi L Haworth, John G Menting, Michael C Lawrence, Andrea J Robinson, Briony E Forbes
The structural transitions required for insulin to activate its receptor and initiate regulation of glucose homeostasis are only partly understood. Here, using ring-closing metathesis, we substitute the A6-A11 disulfide bond of insulin with a rigid, non-reducible dicarba linkage, yielding two distinct stereo-isomers (cis and trans). Remarkably, only the cis isomer displays full insulin potency, rapidly lowering blood glucose in mice (even under insulin-resistant conditions). It also posseses reduced mitogenic activity in vitro...
December 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29030429/activating-mutations-in-quorum-sensing-regulator-rgg2-and-its-conformational-flexibility-in-the-absence-of-an-intermolecular-disulfide-bond
#14
COMPARATIVE STUDY
Reid V Wilkening, Glenn C Capodagli, Atul Khataokar, Kaitlyn M Tylor, Matthew B Neiditch, Michael J Federle
Rap/Rgg/NprR/PlcR/PrgX (RRNPP) quorum-sensing systems use extracellular peptide pheromones that are detected by cytoplasmic receptors to regulate gene expression in firmicute bacteria. Rgg-type receptors are allosterically regulated through direct pheromone binding to control transcriptional activity; however, the receptor activation mechanism remains poorly understood. Previous work has identified a disulfide bond between Cys-45 residues within the homodimer interface of Rgg2 from Streptococcus dysgalactiae (Rgg2Sd )...
December 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29023092/effect-of-the-flexible-regions-of-the-oncoprotein-mouse-double-minute-x-on-inhibitor-binding-affinity
#15
Lingyun Qin, Huili Liu, Rong Chen, Jingjing Zhou, Xiyao Cheng, Yao Chen, Yongqi Huang, Zhengding Su
The oncoprotein MdmX (mouse double minute X) is highly homologous to Mdm2 (mouse double minute 2) in terms of their amino acid sequences and three-dimensional conformations, but Mdm2 inhibitors exhibit very weak affinity for MdmX, providing an excellent model for exploring how protein conformation distinguishes and alters inhibitor binding. The intrinsic conformation flexibility of proteins plays pivotal roles in determining and predicting the binding properties and the design of inhibitors. Although the molecular dynamics simulation approach enables us to understand protein-ligand interactions, the mechanism underlying how a flexible binding pocket adapts an inhibitor has been less explored experimentally...
November 7, 2017: Biochemistry
https://www.readbyqxmd.com/read/28899696/serotonin-2a-receptor-disulfide-bridge-integrity-is-crucial-for-ligand-binding-to-different-signalling-states-but-not-for-its-homodimerization
#16
Alba Iglesias, Marta Cimadevila, Rocío Ailim de la Fuente, María Martí-Solano, María Isabel Cadavid, Marián Castro, Jana Selent, María Isabel Loza, José Brea
The serotonin 2A (5-HT2A) receptor is a G-protein coupled receptor (GPCR) with a conserved disulfide bridge formed by Cys(148) (transmembrane helix 3, TM3) and Cys(227) (extracellular loop 2, ECL-2). We hypothesized that disulfide bridges may determine serotonin 5-HT2A receptor functions such as receptor activation, functional selectivity and ligand recognition. We used the reducing agent dithiothreitol (DTT) to determine how the reduction of disulfide bridges affects radioligand binding, second messenger mobilization and receptor dimerization...
November 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28877869/hemoglobin-polymerization-via-disulfide-bond-formation-in-the-hypoxia-tolerant-turtle-trachemys-scripta-implications-for-antioxidant-defense-and-o-2-transport
#17
Asbjørn G Petersen, Steen V Petersen, Sebastian Frische, Srdja Drakulic, Monika M Golas, Bjoern Sander, Angela Fago
The ability of many reptilian hemoglobins (Hbs) to form high-molecular weight polymers, albeit known for decades, has not been investigated in detail. Given that turtle Hbs often contain a high number of cysteine (Cys), potentially contributing to the red blood cell defense against reactive oxygen species, we have examined whether polymerization of Hb could occur via intermolecular disulfide bonds in red blood cells of freshwater turtle Trachemys scripta, a species that is highly tolerant of hypoxia and oxidative stress...
January 1, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/28825621/inhibitory-effect-of-bovine-lactoferrin-on-catechol-o-methyltransferase
#18
Masayuki Ikeda, Hiroshi Iijima, Ichizo Shinoda, Hiroshi Iwamoto, Yasuhiro Takeda
Lactoferrin (LF) is a well-known multifunctional protein. In this study, we report the inhibitory potency of bovine LF (bLF) on catechol-O-methyltransferase (COMT), which catalyzes methylation of catechol substrates. We found that bLF binds to and inhibits COMT using its N-terminal region. An N-terminal peptide fragment obtained from bLF by trypsin digestion showed a higher inhibitory activity than intact bLF. A synthetic fragment of the bLF N-terminal residues 6-50, with two pairs of disulfide bonds, also showed higher inhibitory activity than intact bLF...
August 19, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28770911/targeting-%C3%AE-cys93-in-hemoglobin-s-with-an-antisickling-agent-possessing-dual-allosteric-and-antioxidant-effects
#19
Tigist Kassa, M B Strader, Akito Nakagawa, Warren M Zapol, Abdu I Alayash
Sickle cell disease (SCD) is an inherited blood disorder caused by a β globin gene mutation of hemoglobin (HbS). The polymerization of deoxyHbS and its subsequent aggregation (into long fibers) is the primary molecular event which leads to red blood cell (RBC) sickling and ultimately hemolytic anemia. We have recently suggested that HbS oxidative toxicity may also contribute to SCD pathophysiology due to its defective pseudoperoxidase activity. As a consequence, a persistently higher oxidized ferryl heme is formed which irreversibly oxidizes "hotspot" residues (particularly βCys93) causing protein unfolding and subsequent heme loss...
September 20, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28761055/a-single-channel-mechanism-for-pharmacological-potentiation-of-glun1-glun2a-nmda-receptors
#20
Divyan A Chopra, Kiran Sapkota, Mark W Irvine, Guangyu Fang, David E Jane, Daniel T Monaghan, Shashank M Dravid
NMDA receptors (NMDARs) contribute to several neuropathological processes. Novel positive allosteric modulators (PAMs) of NMDARs have recently been identified but their effects on NMDAR gating remain largely unknown. To this end, we tested the effect of a newly developed molecule UBP684 on GluN1/GluN2A receptors. We found that UBP684 potentiated the whole-cell currents observed under perforated-patch conditions and slowed receptor deactivation. At the single channel level, UBP684 produced a dramatic reduction in long shut times and a robust increase in mean open time...
July 31, 2017: Scientific Reports
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