Molecular Mechanism of the pH-Dependent Calcium Affinity in Langerin

J.-O. Joswig, J. Anders, H. Zhang, C. Rademacher, B.G. Keller, BioRxiv (2020).

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<jats:title>Abstract</jats:title><jats:p>The C-type lectin receptor langerin plays a vital role in the mammalian defense against invading pathogens. Its function hinges on the affinity to its co-factor Ca<jats:sup>2+</jats:sup> which in turn is regulated by the pH. We studied the structural consequences of pro-tonating the allosteric pH-sensor histidine H294 by molecular dynamics simulations (total simulation time: about 120 μs) and Markov models. We discovered a mechanism in which the signal that the pH has dropped is transferred to the Ca<jats:sup>2+</jats:sup>-binding site without transferring the initial proton. Instead, protonation of H294 unlocks a conformation in which a protonated lysine side-chain forms a hydrogen bond with a Ca<jats:sup>2+</jats:sup>-coordinating aspartic acid. This destabilizes Ca<jats:sup>2+</jats:sup> in the binding pocket, which we probed by steered molecular dynamics. After Ca<jats:sup>2+</jats:sup>-release, the proton is likely transferred to the aspartic acid and stabilized by a dyad with a nearby glutamic acid, triggering a conformational transition and thus preventing Ca<jats:sup>2+</jats:sup>-rebinding.</jats:p>
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Joswig J-O, Anders J, Zhang H, Rademacher C, Keller BG. Molecular Mechanism of the pH-Dependent Calcium Affinity in Langerin. bioRxiv. 2020.
Joswig, J.-O., Anders, J., Zhang, H., Rademacher, C., & Keller, B. G. (2020). Molecular Mechanism of the pH-Dependent Calcium Affinity in Langerin. BioRxiv.
@article{Joswig_Anders_Zhang_Rademacher_Keller_2020, title={Molecular Mechanism of the pH-Dependent Calcium Affinity in Langerin}, journal={bioRxiv}, author={Joswig, Jan-O. and Anders, Jennifer and Zhang, Hengxi and Rademacher, Christoph and Keller, Bettina G.}, year={2020} }
Joswig, Jan-O., Jennifer Anders, Hengxi Zhang, Christoph Rademacher, and Bettina G. Keller. “Molecular Mechanism of the PH-Dependent Calcium Affinity in Langerin.” BioRxiv, 2020.
J.-O. Joswig, J. Anders, H. Zhang, C. Rademacher, and B. G. Keller, “Molecular Mechanism of the pH-Dependent Calcium Affinity in Langerin,” bioRxiv. 2020.
Joswig, Jan-O., et al. “Molecular Mechanism of the PH-Dependent Calcium Affinity in Langerin.” BioRxiv, 2020.

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