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Intradomain Allosteric Network Modulates Calcium Affinity of the C-Type Lectin Receptor Langerin.

Intradomain Allosteric Network Modulates Calcium Affinity of the C-Type Lectin Receptor Langerin.
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Hanske J, Aleksić S, Ballaschk M, Jurk M, Shanina E, Beerbaum M, Schmieder P, Keller BG, Rademacher C,


Hanske J, Aleksić S, Ballaschk M, Jurk M, Shanina E, Beerbaum M, Schmieder P, Keller BG, Rademacher C, (click to view)

Hanske J, Aleksić S, Ballaschk M, Jurk M, Shanina E, Beerbaum M, Schmieder P, Keller BG, Rademacher C,

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Journal of the American Chemical Society 2016 09 08138(37) 12176-86 doi 10.1021/jacs.6b05458

Abstract

Antigen uptake and processing by innate immune cells is crucial to initiate the immune response. Therein, the endocytic C-type lectin receptors serve as pattern recognition receptors, detecting pathogens by their glycan structures. Herein, we studied the carbohydrate recognition domain of Langerin, a C-type lectin receptor involved in the host defense against viruses such as HIV and influenza as well as bacteria and fungi. Using a combination of nuclear magnetic resonance and molecular dynamics simulations, we unraveled the molecular determinants underlying cargo capture and release encoded in the receptor architecture. Our findings revealed receptor dynamics over several time scales associated with binding and release of the essential cofactor Ca(2+) controlled by the coupled motions of two loops. Applying mutual information theory and site-directed mutagenesis, we identified an allosteric intradomain network that modulates the Ca(2+) affinity depending on the pH, thereby promoting fast ligand release.

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