Insights into the mechanism by which interferon-γ basic amino acid clusters mediate protein binding to heparan sulfate
| Autor: | Aline Thomas, Rabia Sadir, Els Saesen, Damien Maurin, Stéphane Sarrazin, Anne Imberty, Cédric Laguri, Hugues Lortat-Jacob |
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| Přispěvatelé: | Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), inconnu, Inconnu, Centre de Recherches sur les Macromolécules Végétales (CERMAV), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Carret, Michèle |
| Rok vydání: | 2013 |
| Předmět: |
Stereochemistry
interaction Sequence (biology) Heparan sulfate Plasma protein binding medicine.disease_cause Biochemistry Catalysis 03 medical and health sciences chemistry.chemical_compound Interferon-gamma 0302 clinical medicine Colloid and Surface Chemistry medicine glycosaminoglycan Molecule [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Binding site Amino Acids ComputingMilieux_MISCELLANEOUS 030304 developmental biology chemistry.chemical_classification 0303 health sciences Mutation Binding Sites Chemistry Proteins General Chemistry Heparin interferon Amino acid Heparitin Sulfate electrostatic 030215 immunology medicine.drug |
| Zdroj: | Journal of the American Chemical Society Journal of the American Chemical Society, American Chemical Society, 2013, 135 (25), pp.9384-90. ⟨10.1021/ja4000867⟩ Journal of the American Chemical Society, 2013, 135 (25), pp.9384-90. ⟨10.1021/ja4000867⟩ Journal of the American Chemical Society, American Chemical Society, 2013, pp.9384-9390 |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/ja4000867⟩ |
| Popis: | International audience; The extensive functional repertoire of heparin and heparan sulfate, which relies on their ability to interact with a large number of proteins, has recently emerged. To understand the forces that drive such interactions the binding of heparin to interferon-γ (IFNγ), used as a model system, was investigated. NMR-based titration experiments demonstrated the involvement of two adjacent cationic domains (D1: KTGKRKR and D2: RGRR), both of which are present within the carboxy-terminal sequence of the cytokine. Kinetic analysis showed that these two domains contribute differently to the interaction: D1 is required to form a complex and constitutes the actual binding site, whereas D2, although unable to associate with heparin by itself, increased the association rate of the binding. These data are consistent with the view that D2, through nonspecific electrostatic forces, places the two molecules in favorable orientations for productive binding within the encounter complex. This mechanism was supported by electrostatic potential analysis and thermodynamic investigations. They showed that D1 association to heparin is driven by both favorable enthalpic and entropic contributions, as expected for a binding sequence, but that D2 gives rise to entropic penalty, which opposes binding in a thermodynamic sense. The binding mechanism described herein, by which the D2 domain kinetically drives the interaction, has important functional consequences and gives a structural framework to better understand how specific are the interactions between proteins and heparin. |
| Databáze: | OpenAIRE |
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