Insights into the molecular basis and mechanism of heme-triggered TLR4 signalling: The role of heme-binding motifs in TLR4 and MD2

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.PMID:37885279 | DOI:10.1111/imm.13708

Source: Immunology - October 27, 2023 Category: Allergy & Immunology Authors: Marie-T Hopp Janine Holze Felicitas Lauber Laura Holtkamp Dhruv C Rathod Maria A Miteva Elisa B Prestes Matthias Geyer B énédicte Manoury Nicolas S Merle Lubka T Roumenina Marcelo T Bozza G ünther Weindl Diana Imhof Source Type: research