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  Molecular Mechanism of the pH-Dependent Calcium Affinity in Langerin

Joswig, J.-O., Anders, J., Zhang, H.-X., Rademacher, C., & Keller, B. G. (2020). Molecular Mechanism of the pH-Dependent Calcium Affinity in Langerin. bioRxiv, 986851. doi:10.1101/2020.03.11.986851.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-EB6A-C Version Permalink: http://hdl.handle.net/21.11116/0000-0005-EB6B-B
Genre: Paper

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 Creators:
Joswig, Jan-O., Author
Anders, Jennifer, Author
Zhang, Heng-Xi1, Author              
Rademacher, Christoph1, Author              
Keller, Bettina G., Author
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1Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_1863300              

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 Abstract: 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 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 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 Ca2+-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.

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Language(s): eng - English
 Dates: 2020-03-122020
 Publication Status: Published in print
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Title: bioRxiv
Source Genre: Journal
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Publ. Info: Cold Spring Harbor Laboratory
Pages: - Volume / Issue: - Sequence Number: 986851 Start / End Page: - Identifier: ZDB: 2766415-6