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.

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Item Type:	Article
Authors/Creators:	Carreras-Puigvert, J. Zitnik, M. Jemth, A.-S. Carter, M. Unterlass, J.E. Hallström, B. Loseva, O. Karem, Z. Calderón-Montaño, J.M. Lindskog, C. Edqvist, P.-H. Matuszewski, D.J. Ait Blal, H. Berntsson, R.P.A. Häggblad, M. Martens, U. Studham, M. Lundgren, B. Wählby, C. Sonnhammer, E.L.L. Lundberg, E. Stenmark, P. Zupan, B. Helleday, T. https://orcid.org/0000-0002-7384-092X
Copyright, Publisher and Additional Information:	© The Author(s) 2017. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Accepted: 6 October 2017 Published (online): 16 November 2017 Published: 16 November 2017
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Oncology (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Human Communication Sciences (Sheffield)
Depositing User:	Symplectic Sheffield
Date Deposited:	08 Apr 2020 11:45
Last Modified:	08 Apr 2020 11:52
Status:	Published
Publisher:	Nature Research
Refereed:	Yes
Identification Number:	10.1038/s41467-017-01642-w
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:159270

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

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