A single evolutionarily divergent mutation determines the different FAD-binding affinities of human and rat NQO1 due to site-specific phosphorylation

0564264 - MBÚ 2023 RIV NL eng J - Journal Article
Luis Pacheco-Garcia, J. - Loginov, Dmitry Sergej - Rizzuti, B. - Vaňková, Pavla - Neira, Jose L. - Kavan, Daniel - Mesa-Torres, N. - Guzzi, R. - Man, Petr - Pey, A. L.
A single evolutionarily divergent mutation determines the different FAD-binding affinities of human and rat NQO1 due to site-specific phosphorylation.
FEBS Letters. Roč. 596, č. 1 (2022), s. 29-41. ISSN 0014-5793. E-ISSN 1873-3468
R&D Projects: GA MŠMT(CZ) ED1.1.00/02.0109
EU Projects: European Commission(XE) 731077 - EU_FT-ICR_MS
Research Infrastructure: CIISB II - 90127
Institutional support: RVO:61388971 ; RVO:86652036
Keywords : epistasis * flavoprotein * molecular evolution * protein phosphorylation
OECD category: Biochemistry and molecular biology
Impact factor: 3.5, year: 2022
Method of publishing: Open access
https://febs.onlinelibrary.wiley.com/doi/10.1002/1873-3468.14238

The phosphomimetic mutation S82D in the cancer-associated, FAD-dependent human NADP(H):quinone oxidoreductase 1 (hNQO1) causes a decrease in flavin-adenine dinucleotide-binding affinity and intracellular stability. We test in this work whether the evolutionarily recent neutral mutation R80H in the vicinity of S82 may alter the strong functional effects of S82 phosphorylation through electrostatic interactions. We show using biophysical and bioinformatic analyses that the reverse mutation H80R prevents the effects of S82D phosphorylation on hNQO1 by modulating the local stability. Consistently, in rat NQO1 (rNQO1) which contains R80, the effects of phosphorylation were milder, resembling the behaviour found in hNQO1 when this residue was humanized in rNQO1 (by the R80H mutation). Thus, apparently neutral and evolutionarily divergent mutations may determine the functional response of mammalian orthologues towards phosphorylation.
Permanent Link: https://hdl.handle.net/11104/0335965