A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family.

Abstract

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.

• Authors: Jordi Carreras-Puigvert, Marinka Zitnik, Ann-Sofie Jemth, Megan Carter, Judith E Unterlass, Björn Hallström, Olga Loseva, Zhir Karem, José Manuel Calderón-Montaño, Cecilia Lindskog, Per-Henrik Edqvist, Damian J Matuszewski, Hammou Ait Blal, Ronnie P A Berntsson, Maria Häggblad, Ulf Martens, Matthew Studham, Bo Lundgren, Carolina Wählby, Erik L L Sonnhammer, Emma Lundberg, Pål Stenmark, Blaz Zupan, Thomas Helleday
• Journal: Nature communications (Nat Commun) Vol. 8 Issue 1 Pg. 1541 (11 16 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 29142246 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Pyrophosphatases

Topics

• A549 Cells
• Cell Line
• Cell Line, Tumor
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Humans
• MCF-7 Cells
• Multigene Family
• Phylogeny
• Pyrophosphatases (classification, genetics, metabolism)
• RNA Interference
• Substrate Specificity
• Nudix Hydrolases