Development of a Chemical Toolset for Studying the Paralog-Specific Function of IRE1

Overview

Journal ACS Chem Biol

Publisher American Chemical Society

Specialties Biochemistry
Biology

Date 2019 Oct 15

PMID 31609569

Citations 14

Authors

Hannah C Feldman

Venkata Narayana Vidadala

Zachary E Potter

Feroz R Papa

Bradley J Backes

Dustin J Maly

Affiliations

Soon will be listed here.

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 IRE1β. While IRE1α has been extensively studied, much less is understood about IRE1β and its role in signaling. In addition, whether the regulation of IRE1β's enzymatic activities varies compared to IRE1α is not known. Here, we show that the RNase domain of IRE1β is enzymatically active and capable of cleaving an XBP1 RNA mini-substrate . Using ATP-competitive inhibitors, we find that, like IRE1α, there is an allosteric relationship between the kinase and RNase domains of IRE1β. This allowed us to develop a novel toolset of both paralog specific and dual-IRE1α/β kinase inhibitors that attenuate RNase activity (KIRAs). Using sequence alignments of IRE1α and IRE1β, we propose a model for paralog-selective inhibition through interactions with nonconserved residues that differentiate the ATP-binding pockets of IRE1α and IRE1β.

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