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  • 1.
    Cheng, Xiaoxiao
    et al.
    Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
    Veverka, Vaclav
    Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom, the Institute of Organic Chemistry and Biochemistry, Flemingovo Namesti 2, 166 10 Prague 6, Czech Republic.
    Radhakrishnan, Anand
    Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
    Waters, Lorna C.
    Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom.
    Muskett, Frederick W.
    Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom.
    Morgan, Sara H.
    Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
    Huo, Jiandong
    Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
    Yu, Chao
    Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
    Evans, Edward J.
    Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
    Leslie, Alasdair J.
    Radcliffe Department of Medicine [Oxford].
    Griffiths, Meryn
    UCB Pharma, Slough SL1 4EN, United Kingdom.
    Stubberfield, Colin
    UCB Pharma, Slough SL1 4EN, United Kingdom.
    Griffin, Robert
    UCB Pharma, Slough SL1 4EN, United Kingdom.
    Henry, Alistair J.
    UCB Pharma, Slough SL1 4EN, United Kingdom.
    Jansson, Andreas
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Ladbury, John E.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Ikemizu, Shinji
    Division of Structural Biology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862 0973, Japan.
    Carr, Mark D.
    Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom.
    Davis, Simon J.
    Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
    Structure and Interactions of the Human Programmed Cell Death 1 Receptor2013In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 17, p. 11771-11785Article in journal (Refereed)
    Abstract [en]

    PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent regulator of immune responses and a promising therapeutic target. The structure and interactions of human PD-1 are, however, incompletely characterized. We present the solution nuclear magnetic resonance (NMR)-based structure of the human PD-1 extracellular region and detailed analyses of its interactions with its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily topology but differs at the edge of the GFCC' sheet, which is flexible and completely lacks a C '' strand. Changes in PD-1 backbone NMR signals induced by ligand binding suggest that, whereas binding is centered on the GFCC' sheet, PD-1 is engaged by its two ligands differently and in ways incompletely explained by crystal structures of mouse PD-1.ligand complexes. The affinities of these interactions and that of PD-L1 with the costimulatory protein B7-1, measured using surface plasmon resonance, are significantly weaker than expected. The 3-4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the 3-fold smaller dissociation rate for PD-L2 binding. Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component. Mathematical simulations based on the biophysical data and quantitative expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1 ligation during interactions of activated T cells with antigen-presenting cells. These findings provide a rigorous structural and biophysical framework for interpreting the important functions of PD-1 and reveal that potent inhibitory signaling can be initiated by weakly interacting receptors.

  • 2.
    Dunne, Aisling
    et al.
    Biochemistry and Biotechnology Institute, Trinity College, Dublin 2, Ireland.
    Ejdebäck, Mikael
    Biochemistry and Biotechnology Institute, Trinity College, Dublin 2, Ireland.
    Ludidi, Phumzile L.
    Department of Biochemistry, University of Cambridge, United Kingdom.
    O'Neill, Luke A. J.
    Biochemistry and Biotechnology Institute, Trinity College, Dublin 2, Ireland.
    Gay, Nicholas J.
    Department of Biochemistry, University of Cambridge, United Kingdom.
    Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD882003In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, no 42, p. 41443-41451Article in journal (Refereed)
    Abstract [en]

    The Toll/interleukin 1 receptor (TIR) domain is a region found in the cytoplasmic tails of members of the Toll-like receptor/interleukin-1 receptor superfamily. The domain is essential for signaling and is also found in the adaptor proteins Mal (MyD88 adaptor-like) and MyD88, which function to couple activation of the receptor to downstream signaling components. Experimental structures of two Toll/interleukin 1 receptor domains reveal a alpha-beta-fold similar to that of the bacterial chemotaxis protein CheY, and other evidence suggests that the adaptors can make heterotypic interactions with both the receptors and themselves. Here we show that the purified TIR domains of Mal and MyD88 can form stable heterodimers and also that Mal homodimers and oligomers are dissociated in the presence of ATP. To identify structural features that may contribute to the formation of signaling complexes, we produced models of the TIR domains from human Toll-like receptor 4 (TLR4), Mal, and MyD88. We found that although the overall fold is conserved the electrostatic surface potentials are quite distinct. Docking studies of the models suggest that Mal and MyD88 bind to different regions in TLRs 2 and 4, a finding consistent with a cooperative role of the two adaptors in signaling. Mal and MyD88 are predicted to interact at a third non-overlapping site, suggesting that the receptor and adaptors may form heterotetrameric complexes. The theoretical model of the interactions is supported by experimental data from glutathione S-transferase pull-downs and co-immunoprecipitations. Neither theoretical nor experimental data suggest a direct role for the conserved proline in the BB-loop in the association of TLR4, Mal, and MyD88. Finally we show a sequence relationship between the Drosophila protein Tube and Mal that may indicate a functional equivalence of these two adaptors in the Drosophila and vertebrate Toll pathways.

  • 3.
    James, John R.
    et al.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    McColl, James
    Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England .
    Oliveira, Marta I.
    Univ Porto, Inst Biol Mol & Celular, Grp Cell Activat & Gene Express, P-4150180 Oporto, Portugal / Univ Porto, Inst Ciencias Biomed Abel Salazar, P-4099003 Oporto, Portugal .
    Dunne, Paul D.
    Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England .
    Huang, Elizabeth
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    Jansson, Andreas
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Nilsson, Patric
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Sleep, David L.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    Goncalves, Carine M.
    Univ Porto, Inst Biol Mol & Celular, Grp Cell Activat & Gene Express, P-4150180 Oporto, Portugal / Univ Porto, Inst Ciencias Biomed Abel Salazar, P-4099003 Oporto, Portugal .
    Morgan, Sara H.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    Felce, James H.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    Mahen, Robert
    Hutchison MRC Res Ctr, Med Res Council Canc Cell Unit, Cambridge CB2 0XZ, England.
    Fernandes, Ricardo A.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    Carmo, Alexandre M.
    Univ Porto, Inst Biol Mol & Celular, Grp Cell Activat & Gene Express, P-4150180 Oporto, Portugal / Univ Porto, Inst Ciencias Biomed Abel Salazar, P-4099003 Oporto, Portugal .
    Klenerman, David
    Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England .
    Davis, Simon J.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    The T Cell Receptor Triggering Apparatus Is Composed of Monovalent or Monomeric Proteins2011In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 37, p. 31993-32001Article in journal (Refereed)
    Abstract [en]

    Understanding the component stoichiometry of the T cell antigen receptor (TCR) triggering apparatus is essential for building realistic models of signal initiation. Recent studies suggesting that the TCR and other signaling-associated proteins are preclustered on resting T cells relied on measurements of the behavior of membrane proteins at interfaces with functionalized glass surfaces. Using fluorescence recovery after photo-bleaching, we show that, compared with the apical surface, the mobility of TCRs is significantly reduced at Jurkat T cell/glass interfaces, in a signaling-sensitive manner. Using two biophysical approaches that mitigate these effects, bioluminescence resonance energy transfer and two-color coincidence detection microscopy, we show that, within the uncertainty of the methods, the membrane components of the TCR triggering apparatus, i.e. the TCR complex, MHC molecules, CD4/Lck and CD45, are exclusively monovalent or monomeric in human T cell lines, implying that TCR triggering depends only on the kinetics of TCR/pMHC interactions. These analyses also showed that constraining proteins to two dimensions at the cell surface greatly enhances random interactions versus those between the membrane and the cytoplasm. Simulations of TCR-pMHC complex formation based on these findings suggest how unclustered TCR triggering-associated proteins might nevertheless be capable of generating complex signaling outputs via the differential recruitment of cytosolic effectors to the cell membrane.

  • 4.
    Kulkarni, Sameer S.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Karlsson, Håkan K. R.
    Karolinska Institutet, Stockholm, Sweden.
    Szekeres, Ferenc
    Karolinska Institutet, Stockholm, Sweden.
    Chibalin, Alexander V.
    Karolinska Institutet, Stockholm, Sweden.
    Krook, Anna
    Karolinska Institutet, Stockholm, Sweden.
    Zierath, Juleen R.
    Karolinska Institutet, Stockholm, Sweden.
    Suppression of 5 '-Nucleotidase Enzymes Promotes AMP-activated Protein Kinase (AMPK) Phosphorylation and Metabolism in Human and Mouse Skeletal Muscle2011In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 40, p. 34567-34574Article in journal (Refereed)
    Abstract [en]

    The 5'-nucleotidase (NT5) family of enzyme dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. We hypothesized that gene silencing of NT5 enzymes to increase the intracellular availability of AMP would increase AMP-activated protein kinase (AMPK) activity and metabolism. We determined the role of cytosolic NT5 in metabolic responses linked to the development of insulin resistance in obesity and type 2 diabetes. Using siRNA to silence NT5C2 expression in cultured human myotubes, we observed a 2-fold increase in the AMP/ATP ratio, a 2.4-fold increase in AMPK phosphorylation (Thr(172)), and a 2.8-fold increase in acetyl-CoA carboxylase phosphorylation (Ser(79)) (p<0.05). siRNA silencing of NT5C2 expression increased palmitate oxidation by 2-fold in the absence and by 8-fold in the presence of 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside. This was paralleled by an increase in glucose transport and a decrease in glucose oxidation, incorporation into glycogen, and lactate release from NT5C2-depleted myotubes. Gene silencing of NT5C1A by shRNA injection and electroporation in mouse tibialis anterior muscle reduced protein content (60%; p<0.05) and increased phosphorylation of AMPK (60%; p<0.05) and acetyl-CoA carboxylase (50%; p<0.05) and glucose uptake (20%; p<0.05). Endogenous expression of NT5C enzymes inhibited basal lipid oxidation and glucose transport in skeletal muscle. Reduction of 5'-nucleotidase expression or activity may promote metabolic flexibility in type 2 diabetes.

  • 5.
    Li, Kaitao
    et al.
    Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, USA.
    Cheng, Xiaoxiao
    Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
    Tilevik, Andreas
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Davis, Simon J.
    Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
    Zhu, Cheng
    Coulter Department of Biomedical Engineering, Woodruff School of Mechanical Engineering, Institute for Bioengineering and Bioscience, Georgia Institute of Technology, USA.
    In situ and in silico kinetic analyses of programmed cell death-1 (PD-1) receptor, programmed cell death ligands, and B7-1 protein interaction network2017In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 292, no 16, p. 6799-6809Article in journal (Refereed)
    Abstract [en]

    Programmed cell death-1 (PD-1) is an inhibitory receptor with an essential role in maintaining peripheral tolerance and is among the most promising immunotherapeutic targets for treating cancer, autoimmunity, and infectious diseases. A complete understanding of the consequences of PD-1 engagement by its ligands, PD-L1 and PD-L2, and of PD-L1 binding to B7-1 requires quantitative analysis of their interactions at the cell surface. We present here the first complete in situ kinetic analysis of the PD-1/PD-ligands/B7-1 system. Consistent with previous solution measurements, we observed higher in situ affinities for human (h) than murine (m) PD-1 interactions, stronger binding of hPD-1 to hPD-L2 than hPD-L1, and comparable binding of mPD-1 to both ligands. However, in contrast to the relatively weak solution affinities, the in situ affinities of PD-1 are as high as those of the T cell receptor for agonist pMHC and of LFA-1 (lymphocyte function-associated antigen 1) for ICAM-1 (intercellular adhesion molecule 1) but significantly lower than that of the B7-1/CTLA-4 interaction, suggesting a distinct basis for PD-1- versus CTLA-4-mediated inhibition. Notably, the in situ interactions of PD-1 are much stronger than that of B7-1 with PD-L1. Overall, the in situ affinity ranking greatly depends on the on-rate instead of the off-rate. In silico simulations predict that PD-1/PD-L1 interactions dominate at interfaces between activated T cells and mature dendritic cells and that these interactions will be highly sensitive to the dynamics of PD-L1 and PD-L2 expression. Our results provide a kinetic framework for better understanding inhibitory PD-1 activity in health and disease.

  • 6.
    Pernestig, Anna-Karin
    et al.
    Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden.
    Melefors, Öjar
    Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden.
    Georgellis, Dimitris
    Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts.
    Identification of UvrY as the cognate response regulator for the BarA sensor kinase in Escherichia coli2001In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 276, no 1, p. 225-231Article in journal (Refereed)
    Abstract [en]

    BarA is a membrane-associated protein that belongs to a subclass of tripartite sensors of the two-component signal transduction system family. In this study, we report that UvrY is the cognate response regulator for BarA of Escherichia coli. This conclusion is based upon homologies with analogous two-component systems and demonstrated by both biochemical and genetic means. We show that the purified BarA protein is able to autophosphorylate when incubated with [gamma-(32)P]ATP but not with [alpha-(32)P]ATP or [gamma-(32)P]GTP. Phosphorylated BarA, in turn, acts as an efficient phosphoryl group donor to UvrY but not to the non-cognate response regulators ArcA, PhoB, or CpxR. The specificity of the transphosphorylation reaction is further supported by the fact that UvrY can receive the phosphoryl group from BarA-P but not from the non-cognate tripartite sensor ArcB-P or ATP. In addition, genetic evidence that BarA and UvrY mediate the same signal transduction pathway is provided by the finding that both uvrY and barA mutant strains exhibit the same hydrogen peroxide hypersensitive phenotype. These results provide the first biochemical evidence as well as genetic support for a link between BarA and UvrY, suggesting that the two proteins constitute a new two-component system for gene regulation in Escherichia coli.

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