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

Pacheco-Garcia J.L. ; Loginov D. ; Rizzuti B. ; Vankova P. ; Neira J.L. ; Kavan D. ; Mesa-Torres N. ; Guzzi R. ; Man P. ; Pey A.L.

Resumen: 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. © 2021 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies

Idioma: Inglés

DOI: 10.1002/1873-3468.14238

Año: 2022

Publicado en: FEBS Letters 596, 1 (2022), 29-41
ISSN: 0014-5793

Factor impacto JCR: 3.5 (2022)

Categ. JCR: BIOPHYSICS rank: 21 / 70 = 0.3 (2022) - Q2 - T1
Categ. JCR: CELL BIOLOGY rank: 121 / 191 = 0.634 (2022) - Q3 - T2
Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 150 / 285 = 0.526 (2022) - Q3 - T2

Factor impacto CITESCORE: 7.0 - Biochemistry, Genetics and Molecular Biology (Q2)

Factor impacto SCIMAGO: 1.276 - Biophysics (Q1) - Genetics (Q1) - Biochemistry (Q1) - Molecular Biology (Q2) - Structural Biology (Q2) - Cell Biology (Q2)

Financiación: info:eu-repo/grantAgreement/ES/MCIU-AEI-FEDER/RTI2018-097991-B-I00
Financiación: info:eu-repo/grantAgreement/ES/MCIU-ERDF/RTI2018-096246-B-I00

Tipo y forma: Article (Published version)