Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-01642-w
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Funding
- European Union [332428]
- Torsten and Ragnar Soderberg Foundation
- Knut and Alice Wallenberg Foundation
- Swedish Research Council
- European Research Council
- Swedish Cancer Society
- Swedish Children's Cancer Foundation
- AFA insurance
- Swedish Pain Relief Foundation
- Cancer Society in Stockholm
- Wenner-Gren Foundations
- Goran Gustafsson Foundation
- Vinnova
- Swedish Foundation for Strategic Research
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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.
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