Development of a Chemical Toolset for Studying the Paralog-Specific Function of IRE1.
ACS Chem Biol
; 14(12): 2595-2605, 2019 12 20.
Article
em En
| MEDLINE
| ID: mdl-31609569
ABSTRACT
The dual kinase endoribonuclease IRE1 is a master regulator of cell fate decisions in cells experiencing endoplasmic reticulum (ER) stress. In mammalian cells, there are two paralogs of IRE1 IRE1α and IRE1ß. While IRE1α has been extensively studied, much less is understood about IRE1ß and its role in signaling. In addition, whether the regulation of IRE1ß's enzymatic activities varies compared to IRE1α is not known. Here, we show that the RNase domain of IRE1ß is enzymatically active and capable of cleaving an XBP1 RNA mini-substrate in vitro. Using ATP-competitive inhibitors, we find that, like IRE1α, there is an allosteric relationship between the kinase and RNase domains of IRE1ß. This allowed us to develop a novel toolset of both paralog specific and dual-IRE1α/ß kinase inhibitors that attenuate RNase activity (KIRAs). Using sequence alignments of IRE1α and IRE1ß, we propose a model for paralog-selective inhibition through interactions with nonconserved residues that differentiate the ATP-binding pockets of IRE1α and IRE1ß.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Serina-Treonina Quinases
/
Endorribonucleases
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
ACS Chem Biol
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos