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Computational investigation of mechanisms for pH modulation of human chloride channels
Open accessPreprint — published as 10.3390/molecules28155753
Abstract
Many transmembrane proteins are modulated by intracellular or extracellular pH. Investigation of pH-dependence generally proceeds by mutagenesis of a wide set of amino acids, guided by properties such as amino acid conservation and structure. This study shows how web-based calculation of pKas allows rapid and effective identification of amino acids of interest with respect to pH-dependence. Commencing with the calcium-activated chloride channel bestrophin 1, the carboxylate ligand structure around calcium sites relaxes in the absence of calcium, consistent with a measured lack of pH-dependence. By contrast, less relaxation in the absence of calcium in TMEM16A, and maintenance of elevated carboxylate sidechain pKas, is suggested to give rise to pH-dependent chloride channel activity. This hypothesis, modulation of calcium/proton coupling and pH-dependent activity through extent of structural relaxation, is shown to apply to the well-characterised cytosolic proteins calmodulin (pH-independent) and calbindin D 9k (pH-dependent). Further application of destabilised ionisable charge sites, or electrostatic frustration, is made to other human chloride channels (that are not calcium-activated), ClC-2, GABA A , and GlyR. Experimentally-determined sites of pH modulation are readily identified. The structure-based tool is freely available, allowing users to focus mutagenesis studies, construct hypothetical proton pathways, and derive hypotheses such as the model for control of pH-dependent calcium activation through structural flexibility. Predicting altered pH-dependence for mutations in ion channel disorders can support experimentation and, ultimately, clinical intervention.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Metadata
- Authors
- Elverson, K., Freeman, S., Manson, F., & Warwicker, J.
- Affiliations
- University of Manchester (GB)
- Corresponding author
- Warwicker, Jim
- Venue
- Molecules
- Publisher
- openRxiv
- Published
- 2022-10-05
- Volume
- 28
- Issue
- 15
- Pages
- 5753-5753
- ISSN
- 1420-3049 (ISSN-L)
- PMC
- PMC10420675
- OpenAlex
- W4385421713
- Cited by
- 5
- References
- 1
- Citations by year
- 2026: 2 · 2025: 3
- FWCI
- 0.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecules (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Sight Research UK (RES 010)
- University of Manchester
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council (BB/V006592/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- pH adjustment, chloride channels, BEST1, TMEM16A, pKa prediction, carboxylate side chains, calcium activation, calmodulin, calbindin-D9k, ClC-2, GABAA receptor, glycine receptor, proton pathway, ion channel disorders, structural flexibility
- MeSH terms
- Bestrophins, Calcium, Humans, Hydrogen-Ion Concentration, Models, Molecular, Chloride Channels
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