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

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 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 and Thomas Helleday ()
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Jordi Carreras-Puigvert: Karolinska Institutet
Marinka Zitnik: University of Ljubljana
Ann-Sofie Jemth: Karolinska Institutet
Megan Carter: Stockholm University
Judith E. Unterlass: Karolinska Institutet
Björn Hallström: Cell Profiling—Affinity Proteomics, Science for Life Laboratory, KTH—Royal Institute of Technology
Olga Loseva: Karolinska Institutet
Zhir Karem: Karolinska Institutet
José Manuel Calderón-Montaño: Karolinska Institutet
Cecilia Lindskog: Genetics and Pathology, Science for Life Laboratory
Per-Henrik Edqvist: Genetics and Pathology, Science for Life Laboratory
Damian J. Matuszewski: Centre for Image Analysis and Science for Life Laboratory, Uppsala University
Hammou Blal: Cell Profiling—Affinity Proteomics, Science for Life Laboratory, KTH—Royal Institute of Technology
Ronnie P. A. Berntsson: Stockholm University
Maria Häggblad: Stockholm University
Ulf Martens: Stockholm University
Matthew Studham: Stockholm University
Bo Lundgren: Stockholm University
Carolina Wählby: Centre for Image Analysis and Science for Life Laboratory, Uppsala University
Erik L. L. Sonnhammer: Stockholm University
Emma Lundberg: Cell Profiling—Affinity Proteomics, Science for Life Laboratory, KTH—Royal Institute of Technology
Pål Stenmark: Stockholm University
Blaz Zupan: University of Ljubljana
Thomas Helleday: Karolinska Institutet

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: 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.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01642-w

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DOI: 10.1038/s41467-017-01642-w

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