A single amino acid deletion in the ER Ca2+sensor STIM1 reverses the in vitro and in vivo effects of the Stormorken syndrome-causing R304W mutation

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60076658%3A12310%2F23%3A43906699" target="_blank" >RIV/60076658:12310/23:43906699 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.science.org/doi/10.1126/scisignal.add0509" target="_blank" >https://www.science.org/doi/10.1126/scisignal.add0509</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1126/scisignal.add0509" target="_blank" >10.1126/scisignal.add0509</a>

Jazyk výsledku

angličtina

Název v původním jazyce

A single amino acid deletion in the ER Ca2+sensor STIM1 reverses the in vitro and in vivo effects of the Stormorken syndrome-causing R304W mutation

Popis výsledku v původním jazyce

Stormorken syndrome is a multiorgan hereditary disease caused by dysfunction of the endoplasmic reticulum (ER) Ca2+ sensor protein STIM1, which forms the Ca2+ release-activated Ca2+ (CRAC) channel together with the plasma membrane channel Orai1. ER Ca2+ store depletion activates STIM1 by releasing the intramolecular &quot;clamp&quot; formed between the coiled coil 1 (CC1) and CC3 domains of the protein, enabling the C terminus to extend and interact with Orai1. The most frequently occurring mutation in patients with Stormorken syndrome is R304W, which destabilizes and extends the STIM1 C terminus independently of ER Ca2+ store depletion, causing constitutive binding to Orai1 and CRAC channel activation. We found that in cis deletion of one amino acid residue, Glu296 (which we called E296del) reversed the pathological effects of R304W. Homozygous Stim1 E296del+R304W mice were viable and phenotypically indistinguishable from wild-type mice. NMR spec-troscopy, molecular dynamics simulations, and cellular experiments revealed that although the R304W muta-tion prevented CC1 from interacting with CC3, the additional deletion of Glu296 opposed this effect by enabling CC1-CC3 binding and restoring the CC domain interactions within STIM1 that are critical for proper CRAC channel function. Our results provide insight into the activation mechanism of STIM1 by clarifying the molecular basis of mutation-elicited protein dysfunction and pathophysiology.

Název v anglickém jazyce

A single amino acid deletion in the ER Ca2+sensor STIM1 reverses the in vitro and in vivo effects of the Stormorken syndrome-causing R304W mutation

Popis výsledku anglicky

Stormorken syndrome is a multiorgan hereditary disease caused by dysfunction of the endoplasmic reticulum (ER) Ca2+ sensor protein STIM1, which forms the Ca2+ release-activated Ca2+ (CRAC) channel together with the plasma membrane channel Orai1. ER Ca2+ store depletion activates STIM1 by releasing the intramolecular &quot;clamp&quot; formed between the coiled coil 1 (CC1) and CC3 domains of the protein, enabling the C terminus to extend and interact with Orai1. The most frequently occurring mutation in patients with Stormorken syndrome is R304W, which destabilizes and extends the STIM1 C terminus independently of ER Ca2+ store depletion, causing constitutive binding to Orai1 and CRAC channel activation. We found that in cis deletion of one amino acid residue, Glu296 (which we called E296del) reversed the pathological effects of R304W. Homozygous Stim1 E296del+R304W mice were viable and phenotypically indistinguishable from wild-type mice. NMR spec-troscopy, molecular dynamics simulations, and cellular experiments revealed that although the R304W muta-tion prevented CC1 from interacting with CC3, the additional deletion of Glu296 opposed this effect by enabling CC1-CC3 binding and restoring the CC domain interactions within STIM1 that are critical for proper CRAC channel function. Our results provide insight into the activation mechanism of STIM1 by clarifying the molecular basis of mutation-elicited protein dysfunction and pathophysiology.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

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

Název periodika

Science Signaling

ISSN

1945-0877

e-ISSN

1937-9145

Svazek periodika

16

Číslo periodika v rámci svazku

771

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

17

Strana od-do

—

Kód UT WoS článku

000937447600001

EID výsledku v databázi Scopus

2-s2.0-85147618029