TY - JOUR
T1 - Structural flexibility of the macrophage dengue virus receptor CLEC5A: Implications for ligand binding and signaling
AU - Watson, Aleksandra A.
AU - Lebedev, Andrey A.
AU - Hall, Benjamin A.
AU - Fenton-May, Angharad E.
AU - Vagin, Alexei A.
AU - Dejnirattisai, Wanwisa
AU - Felce, James
AU - Mongkolsapaya, Juthathip
AU - Palma, Angelina S.
AU - Liu, Yan
AU - Feizi, Ten
AU - Screaton, Gavin R.
AU - Murshudov, Garib N.
AU - O'Callaghan, Christopher A.
N1 - This work was supported by the UK Medical Research Council, National Institute for Health Research Oxford Comprehensive Biomedical Research Centre Program, UK Research Councils Basic Technology Grant GR/S79268 ("Glycoarrays"), Engineering and Physical Research Councils Translational Grant EP/G037604/1, and the Portuguese Foundation for Science and Technology.
We thank Mark Ellis at the Synchrotron Radiation Source, Daresbury, UK and Keith Morris, Paul Young, Aleksandra Flanagan, Jon Grimes, Geoff Sutton, and Mark Sansom for useful conversations. We acknowledge colleagues in the Glycosciences Laboratory: Wengang Chai, Yibing Zhang, Maria Campanero-Rhodes, and Robert Childs for help with microarrays. We acknowledge The Protein-Glycan Interaction Core (H) of The Consortium for Functional Glycomics (funded by National Institutes of Health Grant GM62116 from the NIGMS) for the glycan array analysis.
PY - 2011/7/8
Y1 - 2011/7/8
N2 - The human C-type lectin-like molecule CLEC5A is a critical macrophage receptor for dengue virus. The binding of dengue virus to CLEC5A triggers signaling through the associated adapter molecule DAP12, stimulating proinflammatory cytokine release. We have crystallized an informative ensemble of CLEC5A structural conformers at 1.9-Å resolution and demonstrate how an on-off extension to a β-sheet acts as a binary switch regulating the flexibility of the molecule. This structural information together with molecular dynamics simulations suggests a mechanism whereby extracellular events may be transmitted through the membrane and influence DAP12 signaling. We demonstrate that CLEC5A is homodimeric at the cell surface and binds to dengue virus serotypes 1-4. We used blotting experiments, surface analyses, glycan microarray, and docking studies to investigate the ligand binding potential of CLEC5A with particular respect to dengue virus. This study provides a rational foundation for understanding the dengue virus-macrophage interaction and the role of CLEC5A in dengue virus-induced lethal disease.
AB - The human C-type lectin-like molecule CLEC5A is a critical macrophage receptor for dengue virus. The binding of dengue virus to CLEC5A triggers signaling through the associated adapter molecule DAP12, stimulating proinflammatory cytokine release. We have crystallized an informative ensemble of CLEC5A structural conformers at 1.9-Å resolution and demonstrate how an on-off extension to a β-sheet acts as a binary switch regulating the flexibility of the molecule. This structural information together with molecular dynamics simulations suggests a mechanism whereby extracellular events may be transmitted through the membrane and influence DAP12 signaling. We demonstrate that CLEC5A is homodimeric at the cell surface and binds to dengue virus serotypes 1-4. We used blotting experiments, surface analyses, glycan microarray, and docking studies to investigate the ligand binding potential of CLEC5A with particular respect to dengue virus. This study provides a rational foundation for understanding the dengue virus-macrophage interaction and the role of CLEC5A in dengue virus-induced lethal disease.
UR - http://www.scopus.com/inward/record.url?scp=79959904816&partnerID=8YFLogxK
U2 - 10.1074/jbc.M111.226142
DO - 10.1074/jbc.M111.226142
M3 - Article
C2 - 21566123
AN - SCOPUS:79959904816
VL - 286
SP - 24208
EP - 24218
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 27
ER -
