RT Journal Article
T1 Structural basis of the pleiotropic and specific phenotypic consequences of missense mutations in the multifunctional NAD(P)H:quinone oxidoreductase 1 and their pharmacological rescue.
A1 Pacheco-Garcia, Juan Luis
A1 Anoz-Carbonell, Ernesto
A1 Vankova, Pavla
A1 Kannan, Adithi
A1 Palomino-Morales, Rogelio
A1 Mesa-Torres, Noel
A1 Salido, Eduardo
A1 Man, Petr
A1 Medina, Milagros
A1 Naganathan, Athi N
A1 Pey, Angel L
K1 Disease-causing mutation
K1 Flavoprotein
K1 Ligand binding
K1 Multifunctional protein
K1 NQO1
K1 Post-translational modification
AB The 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.
YR 2021
FD 2021-08-18
LK https://hdl.handle.net/10668/27991
UL https://hdl.handle.net/10668/27991
LA en
DS RISalud
RD Apr 8, 2025