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Mechanism of calmodulin inactivation of the calcium-selective TRP channel TRPV6.


ABSTRACT: Calcium (Ca2+) plays a major role in numerous physiological processes. Ca2+ homeostasis is tightly controlled by ion channels, the aberrant regulation of which results in various diseases including cancers. Calmodulin (CaM)-mediated Ca2+-induced inactivation is an ion channel regulatory mechanism that protects cells against the toxic effects of Ca2+ overload. We used cryo-electron microscopy to capture the epithelial calcium channel TRPV6 (transient receptor potential vanilloid subfamily member 6) inactivated by CaM. The TRPV6-CaM complex exhibits 1:1 stoichiometry; one TRPV6 tetramer binds both CaM lobes, which adopt a distinct head-to-tail arrangement. The CaM carboxyl-terminal lobe plugs the channel through a unique cation-? interaction by inserting the side chain of lysine K115 into a tetra-tryptophan cage at the pore's intracellular entrance. We propose a mechanism of CaM-mediated Ca2+-induced inactivation that can be explored for therapeutic design.

SUBMITTER: Singh AK 

PROVIDER: S-EPMC6093632 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Mechanism of calmodulin inactivation of the calcium-selective TRP channel TRPV6.

Singh Appu K AK   McGoldrick Luke L LL   Twomey Edward C EC   Sobolevsky Alexander I AI  

Science advances 20180815 8


Calcium (Ca<sup>2+</sup>) plays a major role in numerous physiological processes. Ca<sup>2+</sup> homeostasis is tightly controlled by ion channels, the aberrant regulation of which results in various diseases including cancers. Calmodulin (CaM)-mediated Ca<sup>2+</sup>-induced inactivation is an ion channel regulatory mechanism that protects cells against the toxic effects of Ca<sup>2+</sup> overload. We used cryo-electron microscopy to capture the epithelial calcium channel TRPV6 (transient re  ...[more]

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