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Molecular Mechanism of the pH-Dependent Calcium Affinity in Langerin

J.-O. Joswig, J. Anders, H. Zhang, C. Rademacher, B.G. Keller – 2020

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 Ca2+ which in turn is regulated by the pH. We studied the structural consequences of protonating 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 Ca2+-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 Ca2+-coordinating aspartic acid. This destabilizes Ca2+ in the binding pocket, which we probed by steered molecular dynamics. After Ca 2+ -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 Ca2+-rebinding.

Title
Molecular Mechanism of the pH-Dependent Calcium Affinity in Langerin
Author
J.-O. Joswig, J. Anders, H. Zhang, C. Rademacher, B.G. Keller
Date
2020
Identifier
DOI: 10.1101/2020.03.11.986851
Source(s)
Citation
bioRxiv (2020), https://doi.org/10.1101/2020.03.11.986851
Type
Text