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Allosteric disulfide

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https://www.readbyqxmd.com/read/28450398/skeletal-overgrowth-causing-mutations-mimic-an-allosterically-activated-conformation-of-guanylyl-cyclase-b-that-is-inhibited-by-2-4-6-trinitrophenyl-atp
#1
Deborah M Dickey, Neil M Otto, Lincoln R Potter
Activating mutations in the receptor for C-type natriuretic peptide (CNP), guanylyl cyclase B (GC-B, also known as Npr2 or NPR-B), increase cellular cGMP and cause skeletal overgrowth, but how these mutations affect GTP catalysis is poorly understood. The A488P and R655C mutations were compared with the known mutation V883M. Neither mutation affected GC-B concentrations. The A488P mutation decreased the EC50 5-fold, increased Vmax 2.6-fold, and decreased the Km 13-fold, while the R655C mutation decreased the EC50 5-fold, increased the Vmax 2...
April 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28432788/structure-of-fam20a-reveals-a-pseudokinase-featuring-a-unique-disulfide-pattern-and-inverted-atp-binding
#2
Jixin Cui, Qinyu Zhu, Hui Zhang, Michael A Cianfrocco, Andres E Leschziner, Jack E Dixon, Junyu Xiao
Mutations in FAM20A cause tooth enamel defects known as Amelogenesis Imperfecta (AI) and renal calcification. We previously showed that Fam20A is a secretory pathway pseudokinase and allosterically activates the physiological casein kinase Fam20C to phosphorylate secreted proteins important for biomineralization (Cui et al., 2015). Here we report the nucleotide-free and ATP-bound structures of Fam20A. Fam20A exhibits a distinct disulfide bond pattern mediated by a unique insertion region. Loss of this insertion due to abnormal mRNA splicing interferes with the structure and function of Fam20A, resulting in AI...
April 22, 2017: ELife
https://www.readbyqxmd.com/read/28393915/allosteric-inhibition-of-aminopeptidase-n-functions-related-to-tumor-growth-and-virus-infection
#3
César Santiago, Gaurav Mudgal, Juan Reguera, Rosario Recacha, Sébastien Albrecht, Luis Enjuanes, José M Casasnovas
Cell surface aminopeptidase N (APN) is a membrane-bound ectoenzyme that hydrolyzes proteins and peptides and regulates numerous cell functions. APN participates in tumor cell expansion and motility, and is a target for cancer therapies. Small drugs that bind to the APN active site inhibit catalysis and suppress tumor growth. APN is also a major cell entry receptor for coronavirus, which binds to a region distant from the active site. Three crystal structures that we determined of human and pig APN ectodomains defined the dynamic conformation of the protein...
April 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28302727/intersubunit-physical-couplings-fostered-by-the-left-flipper-domain-facilitate-channel-opening-of-p2x4-receptors
#4
Jin Wang, Liang-Fei Sun, Wen-Wen Cui, Wen-Shan Zhao, Xue-Fei Ma, Bin Li, Yan Liu, Yang Yang, You-Min Hu, Li-Dong Huang, Xiao-Yang Cheng, Lingyong Li, Xiang-Yang Lu, Yun Tian, Ye Yu
P2X receptors are ATP-gated trimeric channels with important roles in diverse pathophysiological functions. A detailed understanding of the mechanism underlying the gating process of these receptors is thus fundamentally important and may open new therapeutic avenues. The left flipper (LF) domain of the P2X receptors is a flexible loop structure, and its coordinated motions together with the dorsal fin (DF) domain are crucial for the channel gating of the P2X receptors. However, the mechanism underlying the crucial role of the LF domain in the channel gating remains obscure...
May 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28076818/one-way-allosteric-communication-between-the-two-disulfide-bonds-in-tissue-factor
#5
Beifei Zhou, Philip J Hogg, Frauke Gräter
Tissue factor (TF) is a transmembrane glycoprotein that plays distinct roles in the initiation of extrinsic coagulation cascade and thrombosis. TF contains two disulfide bonds, one each in the N-terminal and C-terminal extracellular domains. The C-domain disulfide, Cys186-Cys209, has a -RHStaple configuration in crystal structures, suggesting that this disulfide carries high pre-stress. The redox state of this disulfide has been proposed to regulate TF encryption/decryption. Ablating the N-domain Cys49-Cys57 disulfide bond was found to increase the redox potential of the Cys186-Cys209 bond, implying an allosteric communication between the domains...
January 10, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28003361/thioredoxin-1-selectively-activates-transglutaminase-2-in-the-extracellular-matrix-of-the-small-intestine-implications-for-celiac-disease
#6
Nicholas M Plugis, Brad A Palanski, Chih-Hisang Weng, Megan Albertelli, Chaitan Khosla
Transglutaminase 2 (TG2) catalyzes transamidation or deamidation of its substrates and is ordinarily maintained in a catalytically inactive state in the intestine and other organs. Aberrant TG2 activity is thought to play a role in celiac disease, suggesting that a better understanding of TG2 regulation could help to elucidate the mechanistic basis of this malady. Structural and biochemical analysis has led to the hypothesis that extracellular TG2 activation involves reduction of an allosteric disulfide bond by thioredoxin-1 (TRX), but cellular and in vivo evidence for this proposal is lacking...
February 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27899437/allosteric-control-of-antibody-prion-recognition-through-oxidation-of-a-disulfide-bond-between-the-ch-and-cl-chains
#7
Jun Zhao, Ruth Nussinov, Buyong Ma
Molecular details of the recognition of disordered antigens by their cognate antibodies have not been studied as extensively as folded protein antigens and much is still unknown. To follow the conformational changes in the antibody and cross-talk between its subunits and with antigens, we performed molecular dynamics (MD) simulations of the complex of Fab and prion-associated peptide in the apo and bound forms. We observed that the inter-chain disulfide bond in constant domains restrains the conformational changes of Fab, especially the loops in the CH1 domain, resulting in inhibition of the cross-talk between Fab subdomains that thereby may prevent prion peptide binding...
January 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/27853286/disulfide-mapping-the-voltage-sensing-mechanism-of-a-voltage-dependent-potassium-channel
#8
Tomohiro Nozaki, Shin-Ichiro Ozawa, Hitomi Harada, Tomomi Kimura, Masanori Osawa, Ichio Shimada
Voltage-dependent potassium (Kv) channels allow for the selective permeability of potassium ions in a membrane potential dependent manner, playing crucial roles in neurotransmission and muscle contraction. Kv channel is a tetramer, in which each subunit possesses a voltage-sensing domain (VSD) and a pore domain (PD). Although several lines of evidence indicated that membrane depolarization is sensed as the movement of helix S4 of the VSD, the detailed voltage-sensing mechanism remained elusive, due to the difficulty of structural analyses at resting potential...
November 17, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27774625/optimal-allosteric-stabilization-sites-using-contact-stabilization-analysis
#9
Alex Dickson, Christopher T Bailey, John Karanicolas
Proteins can be destabilized by a number of environmental factors such as temperature, pH, and mutation. The ability to subsequently restore function under these conditions by adding small molecule stabilizers, or by introducing disulfide bonds, would be a very powerful tool, but the physical principles that drive this stabilization are not well understood. The first problem lies is in choosing an appropriate binding site or disulfide bond location to best confer stability to the active site and restore function...
June 5, 2017: Journal of Computational Chemistry
https://www.readbyqxmd.com/read/27739308/critical-role-of-the-secondary-binding-pocket-in-modulating-the-enzymatic-activity-of-dusp5-toward-phosphorylated-erks
#10
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 from other nuclear DUSPs, such as the presence of a secondary anion-binding site in the proximity of the reaction center and a glutamic acid E264 positioned next to the catalytic cysteine C263, as well as a remote intramolecular disulfide linkage...
November 8, 2016: Biochemistry
https://www.readbyqxmd.com/read/27649076/de-novo-design-of-an-allosteric-metalloprotein-assembly-with-strained-disulfide-bonds
#11
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
https://www.readbyqxmd.com/read/27575053/an-allosteric-disulfide-bond-is-involved-in-enhanced-activation-of-factor-xi-by-protein-disulfide-isomerase
#12
M Zucker, U Seligsohn, A Yeheskel, R Mor-Cohen
Essentials Reduction of three disulfide bonds in factor (F) XI enhances chromogenic substrate cleavage. We measured FXI activity upon reduction and identified a bond involved in the enhanced activity. Reduction of FXI augments FIX cleavage, probably by faster conversion of FXI to FXIa. The Cys362-Cys482 disulfide bond is responsible for FXI enhanced activation upon its reduction. SUMMARY: Background Reduction of factor (F) XI by protein disulfide isomerase (PDI) has been shown to enhance the ability of FXI to cleave its chromogenic substrate...
August 30, 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27573496/a-substrate-driven-allosteric-switch-that-enhances-pdi-catalytic-activity
#13
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...
August 30, 2016: Nature Communications
https://www.readbyqxmd.com/read/27357699/vascular-thiol-isomerases
#14
REVIEW
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
https://www.readbyqxmd.com/read/27255998/the-regulatory-domain-of-human-tryptophan-hydroxylase-1-forms-a-stable-dimer
#15
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
https://www.readbyqxmd.com/read/27233453/thioredoxin-trx1-regulates-cd4-membrane-domain-localization-and-is-required-for-efficient-cd4-dependent-hiv-1-entry
#16
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
https://www.readbyqxmd.com/read/27009680/human-cd4-metastability-is-a-function-of-the-allosteric-disulfide-bond-in-domain-2
#17
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
https://www.readbyqxmd.com/read/26986548/ox133-a-monoclonal-antibody-recognizing-protein-bound-n-ethylmaleimide-for-the-identification-of-reduced-disulfide-bonds-in-proteins
#18
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
https://www.readbyqxmd.com/read/26381939/cysteine-modification-probing-channel-structure-function-and-conformational-change
#19
REVIEW
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
https://www.readbyqxmd.com/read/26379032/cd44-binding-to-hyaluronic-acid-is-redox-regulated-by-a-labile-disulfide-bond-in-the-hyaluronic-acid-binding-site
#20
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
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