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

• Published in: Nature communications Vol. 8; no. 1; pp. 1541 - 17
• Main Authors: Carreras-Puigvert, Jordi, Zitnik, Marinka, Jemth, Ann-Sofie, Carter, Megan, Unterlass, Judith E., Hallström, Björn, Loseva, Olga, Karem, Zhir, Calderón-Montaño, José Manuel, Lindskog, Cecilia, Edqvist, Per-Henrik, Matuszewski, Damian J., Ait Blal, Hammou, Berntsson, Ronnie P. A., Häggblad, Maria, Martens, Ulf, Studham, Matthew, Lundgren, Bo, Wählby, Carolina, Sonnhammer, Erik L. L., Lundberg, Emma, Stenmark, Pål, Zupan, Blaz, Helleday, Thomas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.11.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/114/2391; 631/337; 631/45/607/1164; A-549 cell line; A549 Cells; algorithm; biochemical composition; breast cancer; Cancer; cancer cell line; cancer tissue; Cell cycle; cell cycle regulation; Cell Line; Cell Line, Tumor; cell survival; Cellular signalling networks; colorectal cancer; controlled study; Crystal structure; DNA content; enzyme; enzyme activity; enzyme structure; Epistasis; functional genomics; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; gene interaction; Gene Regulatory Networks; gene silencing; Homeostasis; human; human cell; human tissue; Humanities and Social Sciences; Humans; Hydrolase; Hydrolases; immunohistochemistry; MCF-7 Cells; melanoma; Metabolism; Molecular biology; mRNA processing; multidisciplinary; Multigene Family; Nucleotide sequence; Nudix hydrolase; Nudix Hydrolases; NUDT1 protein; NUDT10 protein; NUDT11 protein; NUDT12 protein; NUDT13 protein; NUDT14 protein; NUDT16 protein; NUDT17 protein; NUDT19 protein; NUDT20 protein; NUDT21 protein; NUDT22 protein; NUDT4 protein; NUDT5 protein; NUDT6 protein; NUDT7 protein; NUDT8 protein; phylogenetic tree; Phylogeny; protein; protein expression; Proteins; Pyrophosphatases - classification; Pyrophosphatases - genetics; Pyrophosphatases - metabolism; Redundancy; RNA Interference; Science; Science (multidisciplinary); sequence alignment; Substrate Specificity; Substrates; tissue microarray; unclassified drug; upregulation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-01642-w

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. The NUDIX hydrolases are known to be involved in several cellular processes and diseases, such as cancer, but remain poorly characterized as a family. Here, the authors provide a comprehensive analysis of the structural, biochemical, and expression properties of 18 human NUDIX proteins, and begin to address their functional inter-relationships.