Journal
BMB REPORTS
Volume 50, Issue 2, Pages 55-57Publisher
KOREAN SOCIETY BIOCHEMISTRY & MOLECULAR BIOLOGY
DOI: 10.5483/BMBRep.2017.50.2.011
Keywords
CD14; Innate immunity; LBP; LPS transfer; Single molecule fluorescence analysis; TLR4/MD2; Transmission electron microscopy
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Funding
- Korean Health Technology R&D Project, Ministry of Health and Welfare [HI15C0508]
- Intelligent Synthetic Biology Center of Global Frontier Project from the Ministry of Science, ICT, and Future Planning
- Korea Health Promotion Institute [HI15C0508020017] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2011-0031955] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Toll-like receptor 4 (TLR4) together with MD2, one of the key pattern recognition receptors for a pathogen-associated molecular pattern, activates innate immunity by recognizing lipopolysaccharide (LPS) of Gram-negative bacteria. Although LBP and CD14 catalyze LPS transfer to the TLR4/MD2 complex, the detail mechanisms underlying this dynamic LPS transfer remain elusive. Using negative-stain electron microscopy, we visualized the dynamic intermediate complexes during LPS transfer-LBP/LPS micelles and ternary CD14/LBP/ LPS micelle complexes. We also reconstituted the entire cascade of LPS transfer to TLR4/MD2 in a total internal reflection fluorescence (TIRF) microscope for a single molecule fluorescence analysis. These analyses reveal longitudinal LBP binding to the surface of LPS micelles and multi-round binding/unbinding of CD14 to single LBP/LPS micelles via key charged residues on LBP and CD14. Finally, we reveal that a single LPS molecule bound to CD14 is transferred to TLR4/MD2 in a TLR4-dependent manner. These discoveries, which clarify the molecular mechanism of dynamic LPS transfer to TLR4/MD2 via LBP and CD14, provide novel insights into the initiation of innate immune responses.
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