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Allosteric disulfide

Marat R Talipov, Jaladhi Nayak, Michael Lepley, Robert D Bongard, Daniel S Sem, Ramani Ramchandran, Rajendra Rathore
DUSP5 is an inducible nuclear dual-specificity phosphatase that specifically interacts with and deactivates extracellular signal-regulated kinases ERK1 and ERK2, which are responsible for cell proliferation, differentiation, and survival. The phosphatase domain (PD) of DUSP5 has unique structural features absent in other nuclear DUSPs, such as presence of a secondary anion-binding site in the proximity to the reaction center and a glutamic acid E264 positioned next to the catalytic cysteine C263, as well as a remote intra-molecular disulfide linkage...
October 14, 2016: Biochemistry
Lewis A Churchfield, Annette Medina-Morales, Jeffrey D Brodin, Alfredo Perez, F Akif Tezcan
A major goal in metalloprotein design is to build protein scaffolds from scratch that allow precise control over metal coordination. A particular challenge in this regard is the construction of allosteric systems in which metal coordination equilibria are coupled to other chemical events that take place elsewhere in the protein scaffold. We previously developed a metal-templated self-assembly strategy (MeTIR) to build supramolecular protein complexes with tailorable interfaces from monomeric building blocks...
October 12, 2016: Journal of the American Chemical Society
Michal Zucker, Uri Seligsohn, Adva Yeheskel, Ronit Mor-Cohen
BACKGROUND: Reduction of factor XI (FXI) by Protein disulfide isomerase (PDI) was shown to enhance FXI ability to cleave its chromogenic substrate. Three disulfide bonds in FXI (Cys118-Cys147, Cys362-Cys482 and Cys321-Cys321) are involved in this augmented activation. OBJECTIVES: To characterize the mechanisms by which PDI enhances FXI activity. METHODS: FXI activity was measured following PDI reduction. Thiols that were exposed in FXI after PDI reduction were labeled by 3-(N-Maleimidopropionyl)-biocytin (MPB) and detected by avidin...
August 30, 2016: Journal of Thrombosis and Haemostasis: JTH
Roelof H Bekendam, Pavan K Bendapudi, Lin Lin, Partha P Nag, Jun Pu, Daniel R Kennedy, Alexandra Feldenzer, Joyce Chiu, Kristina M Cook, Bruce Furie, Mingdong Huang, Philip J Hogg, Robert Flaumenhaft
Protein disulfide isomerase (PDI) is an oxidoreductase essential for folding proteins in the endoplasmic reticulum. The domain structure of PDI is a-b-b'-x-a', wherein the thioredoxin-like a and a' domains mediate disulfide bond shuffling and b and b' domains are substrate binding. The b' and a' domains are connected via the x-linker, a 19-amino-acid flexible peptide. Here we identify a class of compounds, termed bepristats, that target the substrate-binding pocket of b'. Bepristats reversibly block substrate binding and inhibit platelet aggregation and thrombus formation in vivo...
2016: Nature Communications
Robert Flaumenhaft, Bruce Furie
Thiol isomerases are multifunctional enzymes that influence protein structure via their oxidoreductase, isomerase, and chaperone activities. These enzymes localize at high concentrations in the endoplasmic reticulum of all eukaryotic cells where they serve an essential function in folding nascent proteins. However, thiol isomerases can escape endoplasmic retention and be secreted and localized on plasma membranes. Several thiol isomerases including protein disulfide isomerase, ERp57, and ERp5 are secreted by and localize to the membranes of platelets and endothelial cells...
August 18, 2016: Blood
Shengnan Zhang, Cynthia S Hinck, Paul F Fitzpatrick
The three eukaryotic aromatic amino acid hydroxylases phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase have essentially identical catalytic domains and discrete regulatory domains. The regulatory domains of phenylalanine hydroxylase form ACT domain dimers when phenylalanine is bound to an allosteric site. In contrast the regulatory domains of tyrosine hydroxylase form a stable ACT dimer that does not bind the amino acid substrate. The regulatory domain of isoform 1 of human tryptophan hydroxylase was expressed and purified; mutagenesis of Cys64 was required to prevent formation of disulfide-linked dimers...
August 5, 2016: Biochemical and Biophysical Research Communications
Naazneen Moolla, Mark Killick, Maria Papathanasopoulos, Alexio Capovilla
BACKGROUND: CD4 is a glycoprotein expressed on the surfaces of certain immune cells. On lymphocytes, an important function of CD4 is to co-engage Major Histocompatibility Complex (MHC) molecules with the T Cell Receptor (TCR), a process that is essential for antigen-specific activation of T cells. CD4 localizes dynamically into distinct membrane microdomains, an important feature of its immunoregulatory function that has also been shown to influence the efficiency of HIV replication. However, the mechanism by which CD4 localization is regulated and the biological significance of this is incompletely understood...
September 2016: Biochimica et Biophysica Acta
Gavin R Owen, Jennifer A Channell, V Trevor Forsyth, Michael Haertlein, Edward P Mitchell, Alexio Capovilla, Maria Papathanasopoulos, Nichole M Cerutti
CD4 is expressed on the surface of specific leukocytes where it plays a key role in the activation of immunostimulatory T-cells and acts as a primary receptor for HIV-1 entry. CD4 has four ecto-domains (D1-D4) of which D1, D2, and D4 contain disulfide bonds. Although disulfide bonds commonly serve structural or catalytic functions, a rare class of disulfide bonds possessing unusually high dihedral strain energy and a relative ease of reduction can impact protein function by shuffling their redox state. D2 of CD4 possesses one such "allosteric" disulfide...
April 19, 2016: Biochemistry
Lisa-Marie Holbrook, Lai-Shan Kwong, Clive L Metcalfe, Emmanuel Fenouillet, Ian M Jones, A Neil Barclay
In vivo, enzymatic reduction of some protein disulfide bonds, allosteric disulfide bonds, provides an important level of structural and functional regulation. The free cysteine residues generated can be labeled by maleimide reagents, including biotin derivatives, allowing the reduced protein to be detected or purified. During the screening of monoclonal antibodies for those specific for the reduced forms of proteins, we isolated OX133, a unique antibody that recognizes polypeptide resident, N-ethylmaleimide (NEM)-modified cysteine residues in a sequence-independent manner...
May 2016: MAbs
Myles H Akabas
Cysteine substitution has been a powerful tool to investigate the structure and function of proteins. It has been particularly useful for studies of membrane proteins in their native environment, embedded in phospholipid membranes. Among the 20 amino acids, cysteine is uniquely reactive. This reactivity has motivated the synthesis of a wide array of sulfhydryl reactive chemicals. The commercially available array of sulfhydryl reactive reagents has allowed investigators to probe the local steric and electrostatic environment around engineered cysteines and to position fluorescent, paramagnetic and mass probes at specific sites within proteins and for distance measurements between pairs of sites...
2015: Advances in Experimental Medicine and Biology
Helena Kellett-Clarke, Monika Stegmann, A Neil Barclay, Clive Metcalfe
CD44 is the primary leukocyte cell surface receptor for hyaluronic acid (HA), a component of the extracellular matrix. Enzymatic post translational cleavage of labile disulfide bonds is a mechanism by which proteins are structurally regulated by imparting an allosteric change and altering activity. We have identified one such disulfide bond in CD44 formed by Cys77 and Cys97 that stabilises the HA binding groove. This bond is labile on the surface of leukocytes treated with chemical and enzymatic reducing agents...
2015: PloS One
Karin R Chonoles Imlay, Sergey Korshunov, James A Imlay
UNLABELLED: When cystine is added to Escherichia coli, the bacterium becomes remarkably sensitive to hydrogen peroxide. This effect is due to enlarged intracellular pools of cysteine, which can drive Fenton chemistry. Genetic analysis linked the sensitivity to YdjN, a secondary transporter that along with the FliY-YecSC ABC system is responsible for cystine uptake. FliY-YecSC has a nanomolar Km and is essential for import of trace cystine, whereas YdjN has a micromolar Km and is the predominant importer when cystine is more abundant...
December 2015: Journal of Bacteriology
Shawn T Alexander, Thomas Hunter, Sarah Walter, Jin Dong, Derek Maclean, Amos Baruch, Raju Subramanian, James E Tomlinson
AMG 416 is a novel D-amino acid-containing peptide agonist of the calcium-sensing receptor (CaSR) that is being evaluated for the treatment of secondary hyperparathyroidism in chronic kidney disease patients receiving hemodialysis. The principal amino acid residues and their location in the CaSR that accommodate AMG 416 binding and mode of action have not previously been reported. Herein we establish the importance of a pair of cysteine residues, one from AMG 416 and the other from the CaSR at position 482 (Cys482), and correlate the degree of disulfide bond formation between these residues with the pharmacological activity of AMG 416...
November 2015: Molecular Pharmacology
Daniele Raimondi, Gabriele Orlando, Wim F Vranken
Disulfide bonds are crucial for many structural and functional aspects of proteins. They have a stabilizing role during folding, can regulate enzymatic activity and can trigger allosteric changes in the protein structure. Moreover, knowledge of the topology of the disulfide connectivity can be relevant in genomic annotation tasks and can provide long range constraints for ab-initio protein structure predictors. In this paper we describe PhyloCys, a novel unsupervised predictor of disulfide bond connectivity from known cysteine oxidation states...
2015: PloS One
Zhiwei Feng, Guanxing Hu, Shifan Ma, Xiang-Qun Xie
Allosteric modulators of G protein-coupled receptors (GPCRs), which target at allosteric sites, have significant advantages against the corresponding orthosteric compounds including higher selectivity, improved chemical tractability or physicochemical properties, and reduced risk of receptor oversensitization. Bitopic ligands of GPCRs target both orthosteric and allosteric sites. Bitopic ligands can improve binding affinity, enhance subtype selectivity, stabilize receptors, and reduce side effects. Discovering allosteric modulators or bitopic ligands for GPCRs has become an emerging research area, in which the design of allosteric modulators is a key step in the detection of bitopic ligands...
September 2015: AAPS Journal
Tomohiro Nakamura, Olga A Prikhodko, Elaine Pirie, Saumya Nagar, Mohd Waseem Akhtar, Chang-Ki Oh, Scott R McKercher, Rajesh Ambasudhan, Shu-ichi Okamoto, Stuart A Lipton
Nitric oxide (NO) is a gasotransmitter that impacts fundamental aspects of neuronal function in large measure through S-nitrosylation, a redox reaction that occurs on regulatory cysteine thiol groups. For instance, S-nitrosylation regulates enzymatic activity of target proteins via inhibition of active site cysteine residues or via allosteric regulation of protein structure. During normal brain function, protein S-nitrosylation serves as an important cellular mechanism that modulates a diverse array of physiological processes, including transcriptional activity, synaptic plasticity, and neuronal survival...
December 2015: Neurobiology of Disease
Christian Molitor, Stephan Gerhard Mauracher, Sanela Pargan, Rupert L Mayer, Heidi Halbwirth, Annette Rompel
Aurone synthase belongs to the novel group 2 polyphenol oxidases and the presented kinetic characterization suggests a differing aurone biosynthesis in Asteraceae species compared to snapdragon. Aurone synthases (AUS) are polyphenol oxidases (PPO) physiologically involved in the formation of yellow aurone pigments in petals of various Asteraceae species. They catalyze the oxidative conversion of chalcones into aurones. Latent (58.9 kDa) and active (41.6 kDa) aurone synthase from petals of C. grandiflora was purified by a quantitative removal of pigments using aqueous two-phase separation and several subsequent chromatographic steps...
September 2015: Planta
Ester Zito
Oxidative protein folding in the endoplasmic reticulum (ER) is an essential function of eukaryotic cells that requires the relaying of electrons between the proteinaceous components of the pathway. During this process, protein disulfide isomerase (PDI) chaperones oxidatively fold their client proteins before endoplasmic reticulum oxireductin 1 (ERO1) oxidase transfers electrons from the reduced PDI to the terminal acceptor, which is usually molecular oxygen and is subsequently reduced to H2O2. ERO1 function is essential for disulfide bond formation in yeast, whereas in mammals its function is compensated for by alternative pathways...
June 2015: Free Radical Biology & Medicine
Caitlin A Short, Angela T Cao, Molly A Wingfield, Matthew E Doers, Emily M Jobe, Nan Wang, Mark M Levandoski
Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed in the nervous system and are implicated in many normal and pathological processes. The structural determinants of allostery in nAChRs are not well understood. One class of nAChR allosteric modulators, including the small molecule morantel (Mor), acts from a site that is structurally homologous to the canonical agonist site but exists in the β(+)/α(-) subunit interface. We hypothesized that all nAChR subunits move with respect to each other during channel activation and allosteric modulation...
April 2015: Neuropharmacology
Pilar de la Peña, Angeles Machín, Jorge Fernández-Trillo, Pedro Domínguez, Francisco Barros
The N-terminal-most N-tail of the human ether-à-go-go-related gene (hERG) potassium channel is a crucial modulator of deactivation through its interactions with the S4-S5 loop and/or the C-linker/cNBD, leading to a stabilization of the channel's open state. Not only the N-terminal, but also the initial C-terminal region of the channel can modulate the transitions between the open and closed states either by direct or by indirect/allosteric interactions with the gating machinery. However, while a physical proximity of the N-tail to the gating machinery has been demonstrated in the closed state, data about their possible interaction in other channel conformations have been lacking...
August 2015: Pflügers Archiv: European Journal of Physiology
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