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Park, Chan Young
Calcium Dynamics Lab
Research Interests
  • Calcium Signaling, Calcium Channels, Immune, neuroscience, Drug Development, Virus and host cell interaction.

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STIM1 and calmodulin interact with Orai1 to induce Ca2+-dependent inactivation of CRAC channels

Cited 97 times inthomson ciCited 94 times inthomson ci
Title
STIM1 and calmodulin interact with Orai1 to induce Ca2+-dependent inactivation of CRAC channels
Author
Mullins, Franklin M.Park, Chan YoungDolmetsch, Ricardo E.Lewis, Richard S.
Issue Date
2009-09
Publisher
NATL ACAD SCIENCES
Citation
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.106, no.36, pp.15495 - 15500
Abstract
Ca2+-dependent inactivation (CDI) is a key regulator and hallmark of the Ca2+ release-activated Ca2+ (CRAC) channel, a prototypic store-operated Ca2+ channel. Although the roles of the endoplasmic reticulum Ca2+ sensor STIM1 and the channel subunit Orai1 in CRAC channel activation are becoming well understood, the molecular basis of CDI remains unclear. Recently, we defined a minimal CRAC activation domain (CAD; residues 342-448) that binds directly to Orai1 to activate the channel. Surprisingly, CAD-induced CRAC currents lack fast inactivation, revealing a critical role for STIM1 in this gating process. Through truncations of full-length STIM1, we identified a short domain (residues 470-491) C-terminal to CAD that is required for CDI. This domain contains a cluster of 7 acidic amino acids between residues 475 and 483. Neutralization of aspartate or glutamate pairs in this region either reduced or enhanced CDI, whereas the combined neutralization of six acidic residues eliminated inactivation entirely. Based on bioinformatics predictions of a calmodulin (CaM) binding site on Orai1, we also investigated a role for CaM in CDI. We identified a membrane-proximal N-terminal domain of Orai1 (residues 68-91) that binds CaM in a Ca2+-dependent manner and mutations that eliminate CaM binding abrogate CDI. These studies identify novel structural elements of STIM1 and Orai1 that are required for CDI and support a model in which CaM acts in concert with STIM1 and the N terminus of Orai1 to evoke rapid CRAC channel inactivation.
URI
https://scholarworks.unist.ac.kr/handle/201301/7148
URL
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=70349349160
DOI
10.1073/pnas.0906781106
ISSN
0027-8424
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BIO_Journal Papers
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