Disordered regions in the IRE1α ER lumenal domain mediate its stress-induced clustering

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A90242%2F24%3A00139153" target="_blank" >RIV/00216224:90242/24:00139153 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.embopress.org/doi/full/10.1038/s44318-024-00207-0" target="_blank" >https://www.embopress.org/doi/full/10.1038/s44318-024-00207-0</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s44318-024-00207-0" target="_blank" >10.1038/s44318-024-00207-0</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Disordered regions in the IRE1α ER lumenal domain mediate its stress-induced clustering

Popis výsledku v původním jazyce

Conserved signaling cascades monitor protein-folding homeostasis to ensure proper cellular function. One of the evolutionary conserved key players is IRE1, which maintains endoplasmic reticulum (ER) homeostasis through the unfolded protein response (UPR). Upon accumulation of misfolded proteins in the ER, IRE1 forms clusters on the ER membrane to initiate UPR signaling. What regulates IRE1 cluster formation is not fully understood. Here, we show that the ER lumenal domain (LD) of human IRE1 alpha forms biomolecular condensates in vitro. IRE1 alpha LD condensates were stabilized both by binding to unfolded polypeptides as well as by tethering to model membranes, suggesting their role in assembling IRE1 alpha into signaling-competent stable clusters. Molecular dynamics simulations indicated that weak multivalent interactions drive IRE1 alpha LD clustering. Mutagenesis experiments identified disordered regions in IRE1 alpha LD to control its clustering in vitro and in cells. Importantly, dysregulated clustering of IRE1 alpha mutants led to defects in IRE1 alpha signaling. Our results revealed that disordered regions in IRE1 alpha LD control its clustering and suggest their role as a common strategy in regulating protein assembly on membranes.

Název v anglickém jazyce

Disordered regions in the IRE1α ER lumenal domain mediate its stress-induced clustering

Popis výsledku anglicky

Conserved signaling cascades monitor protein-folding homeostasis to ensure proper cellular function. One of the evolutionary conserved key players is IRE1, which maintains endoplasmic reticulum (ER) homeostasis through the unfolded protein response (UPR). Upon accumulation of misfolded proteins in the ER, IRE1 forms clusters on the ER membrane to initiate UPR signaling. What regulates IRE1 cluster formation is not fully understood. Here, we show that the ER lumenal domain (LD) of human IRE1 alpha forms biomolecular condensates in vitro. IRE1 alpha LD condensates were stabilized both by binding to unfolded polypeptides as well as by tethering to model membranes, suggesting their role in assembling IRE1 alpha into signaling-competent stable clusters. Molecular dynamics simulations indicated that weak multivalent interactions drive IRE1 alpha LD clustering. Mutagenesis experiments identified disordered regions in IRE1 alpha LD to control its clustering in vitro and in cells. Importantly, dysregulated clustering of IRE1 alpha mutants led to defects in IRE1 alpha signaling. Our results revealed that disordered regions in IRE1 alpha LD control its clustering and suggest their role as a common strategy in regulating protein assembly on membranes.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

—

Návaznosti

—

Rok uplatnění

2024

Kód důvěrnosti údajů

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

Název periodika

EMBO Journal

ISSN

0261-4189

e-ISSN

—

Svazek periodika

43

Číslo periodika v rámci svazku

20

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

31

Strana od-do

4668-4698

Kód UT WoS článku

001306286100002

EID výsledku v databázi Scopus

2-s2.0-85203078172