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Molecular mechanics investigation of conductance regulation in selective K+ ion channels

Heer, Florian. Molecular mechanics investigation of conductance regulation in selective K+ ion channels. 2016, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12650

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Abstract

Selective ion channels play a crucial role in every aspect of life. The function has been intensively investigated for more than 60 years. Over the years, a clearer picture of the channel functions has emerged. Still many mechanisms are not yet fully understood and some models have to be reevaluated after new insights were gained.
Here I investigated the C-type inactivation mechanism of MthK and its dependence to divalent ions. The effect of the inactivation inducing divalent ion Ca2+ was compared with Mg2+, which did not induce inactivation. Binding of Ca2+ to the selectivity filter impacts on the binding of K+ ions to the selectivity filter and leads to conformational changes putatively associated with inactivation.
A possible mechanism for C-type inactivation was proposed based on KcsA. The conformational changes underlying this mechanism were not observed in other channels, however. We identified inactivation favoring conditions for the channel MthK and a mutant of MthK, which shares a key residue for inactivation in KcsA. Under these conditions, only the mutant inactivated by the described inactivation mechanism, challenging the universality of the mechanism.
Additionally, I investigate the permeation of potassium ions through the selectivity filter of the KcsA channel, which is shown to play a role in the activation process. A closed inner gate lead to a non permeating selectivity filter, in agreement with a pre-activated state with strong ion affinity, increasing the recovery rate from C-type inactivation. Opening of the inner gate reduces the ion binding affinity and increases the channel's conductance. A mutant designed to module steric contact around the selectivity filter is shown to decouple the selectivity filter from the inner gate and to facilitate activation.
Advisors:Schwede, Torsten and Bernèche, Simon and Sthalberg, Henning
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Computational & Systems Biology > Bioinformatics (Schwede)
UniBasel Contributors:Heer, Florian and Schwede, Torsten and Bernèche, Simon
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12650
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (ix, 91 Seiten)
Language:English
Identification Number:
Last Modified:21 Jun 2018 04:30
Deposited On:20 Jun 2018 12:57

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