000118640 001__ 118640 000118640 005__ 20230519145540.0 000118640 0247_ $$2doi$$a10.1016/j.redox.2021.102112 000118640 0248_ $$2sideral$$a127035 000118640 037__ $$aART-2021-127035 000118640 041__ $$aeng 000118640 100__ $$aPacheco-Garcia J.L. 000118640 245__ $$aStructural basis of the pleiotropic and specific phenotypic consequences of missense mutations in the multifunctional NAD(P)H:quinone oxidoreductase 1 and their pharmacological rescue 000118640 260__ $$c2021 000118640 5060_ $$aAccess copy available to the general public$$fUnrestricted 000118640 5203_ $$aThe multifunctional nature of human flavoproteins is critically linked to their ability to populate multiple conformational states. Ligand binding, post-translational modifications and disease-associated mutations can reshape this functional landscape, although the structure-function relationships of these effects are not well understood. Herein, we characterized the structural and functional consequences of two mutations (the cancer-associated P187S and the phosphomimetic S82D) on different ligation states which are relevant to flavin binding, intracellular stability and catalysis of the disease-associated NQO1 flavoprotein. We found that these mutations affected the stability locally and their effects propagated differently through the protein structure depending both on the nature of the mutation and the ligand bound, showing directional preference from the mutated site and leading to specific phenotypic manifestations in different functional traits (FAD binding, catalysis and inhibition, intracellular stability and pharmacological response to ligands). Our study thus supports that pleitropic effects of disease-causing mutations and phosphorylation events on human flavoproteins may be caused by long-range structural propagation of stability effects to different functional sites that depend on the ligation-state and site-specific perturbations. Our approach can be of general application to investigate these pleiotropic effects at the flavoproteome scale in the absence of high-resolution structural models. © 2021 000118640 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/ 000118640 590__ $$a10.787$$b2021 000118640 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b27 / 297 = 0.091$$c2021$$dQ1$$eT1 000118640 592__ $$a2.191$$b2021 000118640 593__ $$aClinical Biochemistry$$c2021$$dQ1 000118640 593__ $$aBiochemistry$$c2021$$dQ1 000118640 594__ $$a16.4$$b2021 000118640 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000118640 700__ $$0(orcid)0000-0002-6649-9153$$aAnoz-Carbonell E.$$uUniversidad de Zaragoza 000118640 700__ $$aVankova P. 000118640 700__ $$aKannan A. 000118640 700__ $$aPalomino-Morales R. 000118640 700__ $$aMesa-Torres N. 000118640 700__ $$aSalido E. 000118640 700__ $$aMan P. 000118640 700__ $$0(orcid)0000-0001-8743-0182$$aMedina M.$$uUniversidad de Zaragoza 000118640 700__ $$aNaganathan A.N. 000118640 700__ $$aPey A.L. 000118640 7102_ $$11011$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Microbiología 000118640 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole. 000118640 773__ $$g46 (2021), 102112 [18 pp]$$pRedox biol.$$tRedox Biology$$x2213-2317 000118640 8564_ $$s16648007$$uhttps://zaguan.unizar.es/record/118640/files/texto_completo.pdf$$yVersión publicada 000118640 8564_ $$s2459307$$uhttps://zaguan.unizar.es/record/118640/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000118640 909CO $$ooai:zaguan.unizar.es:118640$$particulos$$pdriver 000118640 951__ $$a2023-05-18-15:40:07 000118640 980__ $$aARTICLE