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A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family
Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
Univ Ljubljana, Fac Comp & Informat Sci, SI-1000 Ljubljana, Slovenia.; Stanford Univ, Dept Comp Sci, Palo Alto, CA 94305 USA.
Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, no 1, article id 1541Article in journal (Refereed) Published
Abstract [en]

The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes. To a certain extent, their substrate preference redundancies correlate with structural classes, thus linking structure and activity relationships. To elucidate interdependence among the NUDIX hydrolases, we pairwise deplete them generating an epistatic interaction map, evaluate cell cycle perturbations upon knockdown in normal and cancer cells, and analyse their protein and mRNA expression in normal and cancer tissues. Using a novel FUSION algorithm, we integrate all data creating a comprehensive NUDIX enzyme profile map, which will prove fundamental to understanding their biological functionality.

Place, publisher, year, edition, pages
2017. Vol. 8, no 1, article id 1541
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Bioinformatics (Computational Biology)
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URN: urn:nbn:se:uu:diva-333888DOI: 10.1038/s41467-017-01642-wISI: 000415323000014PubMedID: 29142246OAI: oai:DiVA.org:uu-333888DiVA, id: diva2:1158193
Funder
EU, Horizon 2020Swedish Research CouncilTorsten Söderbergs stiftelseKnut and Alice Wallenberg FoundationAFA InsuranceSwedish Cancer SocietySwedish Childhood Cancer FoundationEU, FP7, Seventh Framework Programme, 332428Available from: 2017-11-17 Created: 2017-11-17 Last updated: 2018-02-22Bibliographically approved

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