A Novel Mechanism for Calmodulin Dependent Inactivation of Transient Receptor Potential Vanilloid 6

Bate, Neil and Caves, Rachel E and Skinner, Simon P and Goult, Benjamin T and Basran, Jaswir and Mitcheson, John S and Vuister, Geerten W (2018) A Novel Mechanism for Calmodulin Dependent Inactivation of Transient Receptor Potential Vanilloid 6. Biochemistry, . ISSN 1520-4995. (doi:https://doi.org/10.1021/acs.biochem.7b01286) (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided)

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Abstract

The paralogues TRPV5 and TRPV6 belong to the vanilloid subfamily of the Transient Receptor Potential (TRP) superfamily of ion channels and both play an important role in overall Cahomeostasis. The functioning of the channels centres on a tightly controlled Ca-dependent feedback mechanism where the direct binding of the universal Ca-binding protein calmodulin (CaM) to the channel's C-terminal tail is required for channel inactivation. We have investigated this interaction at the atomic level and propose that under basal cellular [CaCaM is constitutively bound to the channel's C-tail via CaM C-lobe only contacts. When cytosolic [Ca] increases charging the apo CaM N-lobe with Ca, the CaM:TRPV6 complex rearranges and the TRPV6 C-tail further engages the CaM N-lobe via a crucial interaction involving L707. In a cellular context, mutation of L707 significantly increased the rate of channel inactivation. Finally, we present a model for TRPV6 CaM-dependent inactivation, which involves a novel so-called "two-tail" mechanism whereby CaM bridges between two TRPV6 monomers resulting in closure of the channel pore.

Item Type: Article
Uncontrolled keywords: TRPV6 calcium channel NMR ITC electrophysiology Calmodulin
Subjects: Q Science > QH Natural history > QH581.2 Cell Biology
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Ben Goult
Date Deposited: 29 Mar 2018 11:53 UTC
Last Modified: 04 May 2018 11:47 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/66589 (The current URI for this page, for reference purposes)
Goult, Benjamin T: https://orcid.org/0000-0002-3438-2807
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