Bate, N, Caves, RE, Skinner, SP orcid.org/0000-0002-9349-6935 et al. (4 more authors) (2018) A Novel Mechanism for Calmodulin Dependent Inactivation of Transient Receptor Potential Vanilloid 6. Biochemistry, 57 (18). pp. 2611-2622. ISSN 0006-2960
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 Ca2+ homeostasis. The functioning of the channels centres on a tightly controlled Ca2+-dependent feedback mechanism where the direct binding of the universal Ca2+-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 [Ca2+] CaM is constitutively bound to the channel’s C-tail via CaM C-lobe only contacts. When cytosolic [Ca2+] increases charging the apo CaM N-lobe with Ca2+, 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.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biochemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work http://dx.doi/10.1021/acs.biochem.7b01286 |
Keywords: | TRPV6 calcium channel ; NMR ; ITC ; electrophysiology ; Calmodulin |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > NMR (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 08 Mar 2018 11:14 |
Last Modified: | 05 Mar 2019 01:38 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/acs.biochem.7b01286 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:128273 |