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Title: Regulation of TRPV5 channels by Calmodulin
Author: Bokhovchuk, Fedir
ISNI:       0000 0004 5918 9565
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2016
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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.
Supervisor: Vuister, Geerten Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available