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Title: Regulation of TRPV5 channels by Calmodulin
Authors: Bokhovchuk, Fedir
Supervisors: Vuister, Geerten
First Published: 30-Jun-2016
Award date: 30-Jun-2016
Abstract: The epithelial selective Ca²⁺ channel transient receptor potential vanilloid 5 channel (TRPV5) constitutes the apical entry gate for active Ca2+ reabsorption in the kidney. The activity of TRPV5 and, therefore, Ca²⁺ influx, is tightly regulated by various hormonal stimuli mediated by interactions with numerous intracellular binding partners. Previously, it was shown that the Ca²⁺-sensor Calmodulin (CaM) is directly involved in the Ca²⁺-induced inactivation of TRPV5; however, the structural basis of this mechanism remained unclear. A series of putative CaM-binding sites was identified in the TRPV5 monomer and it was shown by electrophysiology that the C-terminal distal binding site is essential for the inactivation of the channel. This thesis reports on the investigation of molecular and structural aspects of the interaction between the TRPV5 C-terminus and CaM. Using high-resolution NMR spectroscopy together with a set of complimentary methods, the CaM:TRPV5 complexes were studied in detail and the distinct roles of the CaM N- and C- domains were demonstrated. The structure of a CaM mutant, mimicking a low Ca²⁺ state, in complex with the TRPV5 peptide was determined de novo by NMR spectroscopy. Also, the interaction between the proximal C-terminal region of TRPV5 and membrane phospholipids was studied. The combined data provide the mechanistic basis for a new model of the Ca²⁺/CaM-dependent TRPV5 inactivation.
Type: Thesis
Rights: Copyright © the author. All rights reserved.
Appears in Collections:Leicester Theses
Theses, Dept. of Molecular and Cell Biology

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