Application of immobilized ATP to the study of NLRP inflammasomes

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dc.contributor.authorLiao, Kuo Chieh
dc.contributor.authorSandall, Christina F.
dc.contributor.authorCarlson, David A.
dc.contributor.authorUlke-Lemée, Annegret
dc.contributor.authorPlatnich, Jaye
dc.contributor.authorHughes, Philip Floyd
dc.contributor.authorMuruve, Daniel A.
dc.contributor.authorHaystead, Timothy Arthur James
dc.contributor.authorMacDonald, Justin Anthony
dc.date.accessioned2019-04-24T16:50:52Z
dc.date.available2019-04-24T16:50:52Z
dc.date.issued2019-01-11
dc.description.abstractThe NLRP proteins are a subfamily of the NOD-like receptor (NLR) innate immune sensors that possess an ATP-binding NACHT domain. As the most well-studied member, NLRP3 can initiate the assembly process of a multiprotein complex, termed the inflammasome, upon detection of a wide range of microbial products and endogenous danger signals and results in the activation of pro-caspase-1, a cysteine protease that regulates multiple host defense pathways including cytokine maturation. Dysregulated NLRP3 activation contributes to inflammation and the pathogenesis of several chronic diseases, and the ATP-binding properties of NLRPs are thought to be critical for inflammasome activation. In light of this, we examined the utility of immobilized ATP matrices in the study of NLRP inflammasomes. Using NLRP3 as the prototypical member of the family, P-linked ATP Sepharose was determined to be a highly-effective capture agent. In subsequent examinations, P-linked ATP Sepharose was used as an enrichment tool to enable the effective profiling of NLRP3-biomarker signatures with selected reaction monitoring-mass spectrometry (SRM-MS). Finally, ATP Sepharose was used in combination with a fluorescence-linked enzyme chemoproteomic strategy (FLECS) screen to identify potential competitive inhibitors of NLRP3. The identification of a novel benzo[d]imidazol-2-one inhibitor that specifically targets the ATP-binding and hydrolysis properties of the NLRP3 protein implies that ATP Sepharose and FLECS could be applied other NLRPs as well.en_US
dc.description.grantingagencyCanadian Institutes of Health Research - Foundation Schemeen_US
dc.identifier.citationLiao, K. C., Sandall, C. F., Carlson, D. A., Ulke-Lemée, A., Platnich, J., Hughes, P. F., ... MacDonald, J. A. (2019). Application of immobilized ATP to the study of NLRP inflammasomes. 1-42. http://dx.doi.org/10.1016/j.abb.2018.12.031en_US
dc.identifier.doihttp://dx.doi.org/10.1016/j.abb.2018.12.031en_US
dc.identifier.grantnumberHealth Challenges in Chronic Disease Signature Initiative (#THC-13523)en_US
dc.identifier.urihttp://hdl.handle.net/1880/110194
dc.identifier.urihttps://doi.org/10.11575/PRISM/43852
dc.language.isoengen_US
dc.publisher.departmentBiochemistry & Molecular Biologyen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen_US
dc.publisher.institutionDuke Universityen_US
dc.subjectdrug discoveryen_US
dc.subjectfluorescence-linked enzyme chemoproteomic strategy, FLECSen_US
dc.subjectinflammasomeen_US
dc.subjectLeucine rich repeat and pyrin domain containing-3; NLRPen_US
dc.subjectNucleotide-binding oligomerization domainen_US
dc.subjectSelected reaction monitoring mass spectrometry, SRM-MSen_US
dc.titleApplication of immobilized ATP to the study of NLRP inflammasomesen_US
dc.typejournal articleen_US
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