Your browser doesn't support javascript.
loading
Insights into the molecular basis and mechanism of heme-triggered TLR4 signalling: The role of heme-binding motifs in TLR4 and MD2.
Hopp, Marie-T; Holze, Janine; Lauber, Felicitas; Holtkamp, Laura; Rathod, Dhruv C; Miteva, Maria A; Prestes, Elisa B; Geyer, Matthias; Manoury, Bénédicte; Merle, Nicolas S; Roumenina, Lubka T; Bozza, Marcelo T; Weindl, Günther; Imhof, Diana.
Afiliação
  • Hopp MT; Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute, University of Bonn, Bonn, Germany.
  • Holze J; Department of Chemistry, Institute of Integrated Natural Sciences, University of Koblenz, Koblenz, Germany.
  • Lauber F; Pharmacology and Toxicology, Pharmaceutical Institute, University of Bonn, Bonn, Germany.
  • Holtkamp L; Pharmacology and Toxicology, Pharmaceutical Institute, University of Bonn, Bonn, Germany.
  • Rathod DC; Pharmacology and Toxicology, Pharmaceutical Institute, University of Bonn, Bonn, Germany.
  • Miteva MA; Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute, University of Bonn, Bonn, Germany.
  • Prestes EB; CNRS UMR 8038 CiTCoM, Université de Paris, Faculté de Pharmacie de Paris, Paris, France.
  • Geyer M; INSERM U 1268 Medicinal Chemistry and Translational Research, Paris, France.
  • Manoury B; Laboratório de Inflamação e Imunidade, Departamento de Imunologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
  • Merle NS; Institute of Structural Biology, University of Bonn, Bonn, Germany.
  • Roumenina LT; Institut Necker Enfants Malades, INSERM U1151-CNRS UMR8253, Université Paris Cité, Faculté de médecine Necker, Paris, France.
  • Bozza MT; Centre de Recherche des Cordeliers, UMR_S 1138, INSERM, Paris, France.
  • Weindl G; Centre de Recherche des Cordeliers, Sorbonne Universités, Paris, France.
  • Imhof D; Centre de Recherche des Cordeliers, Université Paris Descartes, Paris, France.
Immunology ; 171(2): 181-197, 2024 Feb.
Article em En | MEDLINE | ID: mdl-37885279
ABSTRACT
Haemolytic disorders, such as sickle cell disease, are accompanied by the release of high amounts of labile heme into the intravascular compartment resulting in the induction of proinflammatory and prothrombotic complications in affected patients. In addition to the relevance of heme-regulated proteins from the complement and blood coagulation systems, activation of the TLR4 signalling pathway by heme was ascribed a crucial role in the progression of these pathological processes. Heme binding to the TLR4-MD2 complex has been proposed recently, however, essential mechanistic information of the processes at the molecular level, such as heme-binding kinetics, the heme-binding capacity and the respective heme-binding sites (HBMs) is still missing. We report the interaction of TLR4, MD2 and the TLR4-MD2 complex with heme and the consequences thereof by employing biochemical, spectroscopic, bioinformatic and physiologically relevant approaches. Heme binding occurs transiently through interaction with up to four HBMs in TLR4, two HBMs in MD2 and at least four HBMs in their complex. Functional studies highlight that mutations of individual HBMs in TLR4 preserve full receptor activation by heme, suggesting that heme interacts with TLR4 through different binding sites independently of MD2. Furthermore, we confirm and extend the major role of TLR4 for heme-mediated cytokine responses in human immune cells.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Receptor 4 Toll-Like Limite: Humans Idioma: En Revista: Immunology Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Receptor 4 Toll-Like Limite: Humans Idioma: En Revista: Immunology Ano de publicação: 2024 Tipo de documento: Article