CRAC channel opening is determined by a series of Orai1 gating checkpoints in the transmembrane and cytosolic regions

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F21%3A00549327" target="_blank" >RIV/61388971:_____/21:00549327 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11320/21:10438873

Result on the web

<a href="https://www.jbc.org/article/S0021-9258(20)00339-7/pdf" target="_blank" >https://www.jbc.org/article/S0021-9258(20)00339-7/pdf</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1074/jbc.RA120.015548" target="_blank" >10.1074/jbc.RA120.015548</a>

Result language

angličtina

Original language name

CRAC channel opening is determined by a series of Orai1 gating checkpoints in the transmembrane and cytosolic regions

Original language description

The initial activation step in the gating of ubiquitously expressed Orai1 calcium (Ca2+) ion channels represents the activation of the Ca2+-sensor protein STIM1 upon Ca2+ store depletion of the endoplasmic reticulum. Previous studies using constitutively active Orai1 mutants gave rise to, but did not directly test, the hypothesis that STIM1-mediated Orai1 pore opening is accompanied by a global conformational change of all Orai transmembrane domain (TM) helices within the channel complex. We prove that a local conformational change spreads omnidirectionally within the Orai1 complex. Our results demonstrate that these locally induced global, opening-permissive TM motions are indispensable for pore opening and require clearance of a series of Orai1 gating checkpoints. We discovered these gating checkpoints in the middle and cytosolic extended TM domain regions. Our findings are based on a library of double point mutants that contain each one loss-of-function with one gain-of-function point mutation in a series of possible combinations. We demonstrated that an array of loss-of-function mutations are dominant over most gain-of-function mutations within the same as well as of an adjacent Orai subunit. We further identified inter- and intramolecular salt-bridge interactions of Orai subunits as a core element of an opening-permissive Orai channel architecture. Collectively, clearance and synergistic action of all these gating checkpoints are required to allow STIM1 coupling and Orai1 pore opening. Our results unravel novel insights in the preconditions of the unique fingerprint of CRAC channel activation, provide a valuable source for future structural resolutions, and help to understand the molecular basis of disease-causing mutations.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10606 - Microbiology

Project

<a href="/en/project/GJ19-20728Y" target="_blank" >GJ19-20728Y: Modeling activation of human calcium release-activated channels.</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2021

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Biological Chemistry

ISSN

0021-9258

e-ISSN

1083-351X

Volume of the periodical

296

Issue of the periodical within the volume

JAN-JUN 2021

Country of publishing house

NL - THE KINGDOM OF THE NETHERLANDS

Number of pages

21

Pages from-to

100224

UT code for WoS article

000672866400202

EID of the result in the Scopus database

2-s2.0-85101713436