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

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: IRE1? and IRE1?. While IRE1? has been extensively studied, much less is understood about IRE1? and its role in signaling. In addition, whether the regulation of IRE1?'s enzymatic activities varies compared to IRE1? is not known. Here, we show that the RNase domain of IRE1? is enzymatically active and capable of cleaving an XBP1 RNA mini-substrate in vitro. Using ATP-competitive inhibitors, we find that, like IRE1?, there is an allosteric relationship between the kinase and RNase domains of IRE1?. This allowed us to develop a novel toolset of both paralog specific and dual-IRE1?/? kinase inhibitors that attenuate RNase activity (KIRAs). Using sequence alignments of IRE1? and IRE1?, we propose a model for paralog-selective inhibition through interactions with nonconserved residues that differentiate the ATP-binding pockets of IRE1? and IRE1?.

SUBMITTER: Feldman HC

PROVIDER: S-EPMC6925334 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Feldman Hannah C HC Vidadala Venkata Narayana VN Potter Zachary E ZE Papa Feroz R FR Backes Bradley J BJ Maly Dustin J DJ

ACS chemical biology 20191014 12

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 capabl ...[more]

PMID: 31609569

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Project description:BackgroundAfter many years of research on software repositories, the knowledge for building mature, reusable tools that perform data retrieval, storage and basic analytics is readily available. However, there is still room to improvement in the area of reusable tools implementing this knowledge.GoalTo produce a reusable toolset supporting the most common tasks when retrieving, curating and visualizing data from software repositories, allowing for the easy reproduction of data sets ready for more complex analytics, and sparing the researcher or the analyst of most of the tasks that can be automated.MethodUse our experience in building tools in this domain to identify a collection of scenarios where a reusable toolset would be convenient, and the main components of such a toolset. Then build those components, and refine them incrementally using the feedback from their use in both commercial, community-based, and academic environments.ResultsGrimoireLab, an efficient toolset composed of five main components, supporting about 30 different kinds of data sources related to software development. It has been tested in many environments, for performing different kinds of studies, and providing different kinds of services. It features a common API for accessing the retrieved data, facilities for relating items from different data sources, semi-structured storage for easing later analysis and reproduction, and basic facilities for visualization, preliminary analysis and drill-down in the data. It is also modular, making it easy to support new kinds of data sources and analysis.ConclusionsWe present a mature toolset, widely tested in the field, that can help to improve the situation in the area of reusable tools for mining software repositories. We show some scenarios where it has already been used. We expect it will help to reduce the effort for doing studies or providing services in this area, leading to advances in reproducibility and comparison of results.

Dataset Information

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

Publications

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

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