2. Academic Validation
  3. A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family

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

  • Nat Commun. 2017 Nov 16;8(1):1541. doi: 10.1038/s41467-017-01642-w.
Jordi Carreras-Puigvert 1,  Marinka Zitnik 2 3,  Ann-Sofie Jemth 4,  Megan Carter 5,  Judith E Unterlass 4,  Björn Hallström 6,  Olga Loseva 4,  Zhir Karem 4,  José Manuel Calderón-Montaño 4,  Cecilia Lindskog 7,  Per-Henrik Edqvist 7,  Damian J Matuszewski 8,  Hammou Ait Blal 6,  Ronnie P A Berntsson 5,  Maria Häggblad 9,  Ulf Martens 9,  Matthew Studham 10,  Bo Lundgren 9,  Carolina Wählby 8,  Erik L L Sonnhammer 10,  Emma Lundberg 6,  Pål Stenmark 5,  Blaz Zupan 2 11,  Thomas Helleday 12
Affiliations

Affiliations

  • 1 Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Molecular Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 171 65, Sweden. jordi.carreras.puigvert@scilifelab.se.
  • 2 Faculty of Computer and Information Science, University of Ljubljana, SI-1000, Ljubljana, Slovenia.
  • 3 Department of Computer Science, Stanford University, Palo Alto, CA, 94305, USA.
  • 4 Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Molecular Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 171 65, Sweden.
  • 5 Department of Biochemistry and Biophysics, Stockholm University, 106 91, Stockholm, Sweden.
  • 6 Cell Profiling-Affinity Proteomics, Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, 17165, Sweden.
  • 7 Department of Immunology, Genetics and Pathology, Science for Life Laboratory, 751 85, Uppsala, Sweden.
  • 8 Centre for Image Analysis and Science for Life Laboratory, Uppsala University, Uppsala, 751 05, Sweden.
  • 9 Biochemical and Cellular Screening Facility, Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, 171 65, Sweden.
  • 10 Stockholm Bioinformatics Center, Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Box 1031, 171 21, Solna, Sweden.
  • 11 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 12 Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Molecular Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 171 65, Sweden. thomas.helleday@scilifelab.se.
PMID: 29142246 DOI: 10.1038/s41467-017-01642-w
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.

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