Luminal STIM1 Mutants that Cause Tubular Aggregate Myopathy Promote Autophagic Processes

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F20%3A00533047" target="_blank" >RIV/61388971:_____/20:00533047 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.mdpi.com/1422-0067/21/12/4410" target="_blank" >https://www.mdpi.com/1422-0067/21/12/4410</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/ijms21124410" target="_blank" >10.3390/ijms21124410</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Luminal STIM1 Mutants that Cause Tubular Aggregate Myopathy Promote Autophagic Processes

Popis výsledku v původním jazyce

Stromal interaction molecule 1 (STIM1) is a ubiquitously expressed Ca(2+)sensor protein that induces permeation of Orai Ca(2+)channels upon endoplasmic reticulum Ca2+-store depletion. A drop in luminal Ca(2+)causes partial unfolding of the N-terminal STIM1 domains and thus initial STIM1 activation. We compared the STIM1 structure upon Ca(2+)depletion from our molecular dynamics (MD) simulations with a recent 2D NMR structure. Simulation- and structure-based results showed unfolding of two alpha-helices in the canonical and in the non-canonical EF-hand. Further, we structurally and functionally evaluated mutations in the non-canonical EF-hand that have been shown to cause tubular aggregate myopathy. We found these mutations to cause full constitutive activation of Ca2+-release-activated Ca(2+)currents (I-CRAC) and to promote autophagic processes. Specifically, heterologously expressed STIM1 mutations in the non-canonical EF-hand promoted translocation of the autophagy transcription factors microphthalmia-associated transcription factor (MITF) and transcription factor EB (TFEB) into the nucleus. These STIM1 mutations additionally stimulated an enhanced production of autophagosomes. In summary, mutations in STIM1 that cause structural unfolding promoted Ca(2+)down-stream activation of autophagic processes.

Název v anglickém jazyce

Luminal STIM1 Mutants that Cause Tubular Aggregate Myopathy Promote Autophagic Processes

Popis výsledku anglicky

Stromal interaction molecule 1 (STIM1) is a ubiquitously expressed Ca(2+)sensor protein that induces permeation of Orai Ca(2+)channels upon endoplasmic reticulum Ca2+-store depletion. A drop in luminal Ca(2+)causes partial unfolding of the N-terminal STIM1 domains and thus initial STIM1 activation. We compared the STIM1 structure upon Ca(2+)depletion from our molecular dynamics (MD) simulations with a recent 2D NMR structure. Simulation- and structure-based results showed unfolding of two alpha-helices in the canonical and in the non-canonical EF-hand. Further, we structurally and functionally evaluated mutations in the non-canonical EF-hand that have been shown to cause tubular aggregate myopathy. We found these mutations to cause full constitutive activation of Ca2+-release-activated Ca(2+)currents (I-CRAC) and to promote autophagic processes. Specifically, heterologously expressed STIM1 mutations in the non-canonical EF-hand promoted translocation of the autophagy transcription factors microphthalmia-associated transcription factor (MITF) and transcription factor EB (TFEB) into the nucleus. These STIM1 mutations additionally stimulated an enhanced production of autophagosomes. In summary, mutations in STIM1 that cause structural unfolding promoted Ca(2+)down-stream activation of autophagic processes.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/GJ19-20728Y" target="_blank" >GJ19-20728Y: Modelování aktivace lidských vápníkových kanálů zavislých na koncentraci uvolněneho vapníku.</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

Kód důvěrnosti údajů

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

Název periodika

International Journal of Molecular Sciences

ISSN

1422-0067

e-ISSN

—

Svazek periodika

21

Číslo periodika v rámci svazku

12

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

15

Strana od-do

4410

Kód UT WoS článku

000550162400001

EID výsledku v databázi Scopus

2-s2.0-85087010833