Preprint Article Version 1 This version is not peer-reviewed

A Dynamic Core in Human NQO1 Controls the Functional and Stability Effects of Ligand Binding and Their Communication across the Enzyme Dimer

Version 1 : Received: 23 October 2019 / Approved: 24 October 2019 / Online: 24 October 2019 (15:41:46 CEST)

A peer-reviewed article of this Preprint also exists.

Vankova, P.; Salido, E.; Timson, D.J.; Man, P.; Pey, A.L. A Dynamic Core in Human NQO1 Controls the Functional and Stability Effects of Ligand Binding and Their Communication across the Enzyme Dimer. Biomolecules 2019, 9, 728. Vankova, P.; Salido, E.; Timson, D.J.; Man, P.; Pey, A.L. A Dynamic Core in Human NQO1 Controls the Functional and Stability Effects of Ligand Binding and Their Communication across the Enzyme Dimer. Biomolecules 2019, 9, 728.

Journal reference: Biomolecules 2019, 9, 728
DOI: 10.3390/biom9110728

Abstract

Human NAD(P)H:quinone oxidoreductase 1 (NQO1) is a multi-functional protein whose alteration is associated with cancer, Parkinson´s and Alzheimer´s diseases. NQO1 displays a remarkable functional chemistry, capable of binding different functional ligands that modulate its activity, stability and interaction with proteins and nucleic acids. Our understanding on this functional chemistry is limited by the difficulty of obtaining structural and dynamic information on many of these states. Herein, we have used hydrogen/deuterium exchange monitored by mass-spectrometry (HDXMS) to investigate the structural dynamics of NQO1 in three ligation states: without ligands (NQO1apo), with FAD (NQO1holo) and with FAD and the inhibitor dicoumarol (NQO1dic). We show that NQO1apo has a minimally stable folded core holding the protein dimer and with FAD and dicoumarol ligand binding sites populating binding non-competent conformations. Binding of FAD significantly decreases protein dynamics and stabilizes the FAD and dicoumarol binding sites as well as the monomer:monomer interface. Dicoumarol binding further stabilizes all three functional sites, a result not previously anticipated by available crystallographic models. Our work provides an experimental perspective into the communication of stability effects through the NQO1 dimer, valuable to understand at the molecular level the effects of disease-associated variants, post-translation modifications and ligand binding cooperativity in NQO1.

Subject Areas

protein structural dynamics; NQO1; ligand binding; protein stability; allostery; protein degradation

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