Erratum: Conformational dynamics is key to understanding loss-of-function of NQO1 cancer-associated polymorphisms and its correction by pharmacological ligands

Medina‐Carmona, Encarnación; Palomino-Morales, Rogelio; Fuchs, Julian E.; Padín-González, Esperanza; Mesa‐Torres, Noel; Salido, Eduardo; Timson, David J.; Pey, Ángel L.

doi:10.1038/srep21939

Cited by 2 publications

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“…Mutational effects on FAD binding affinity (ΔΔG FAD ) and proteolysis rates (ΔΔG PROT ) with thermolysin have previously been shown to correlate well ( Medina-Carmona et al, 2017a ; Medina-Carmona et al, 2019b ; Pacheco-García et al, 2020 ). The site for initial cleavage by thermolysin (TCS) is generally between Ser72–Val73, close to the FAD binding site ( Medina-Carmona et al, 2016 ). All the variants investigated showed proteolysis patterns that were similar to that of WT NQO1 ( Supplementary Figure S5 ).…”

Section: Resultsmentioning

confidence: 99%

“…We have recently shown that ligand binding and variant effects on stability propagate to long distances in the native state, affecting different functional features in a counterintuitive fashion ( Medina-Carmona et al, 2016 ; Pey, 2018 ; Medina-Carmona et al, 2019a ; Vankova et al, 2019 ; Pacheco-García et al, 2020 ; Pacheco-Garcia et al, 2021 ; Pacheco-Garcia et al, 2022a ). Therefore, NQO1 represents a challenging and biomedically relevant system to compare the performance of computational and experimental methods to explain and to predict genotype-phenotype in a large-scale for a multi-functional protein.…”

Section: Introductionmentioning

confidence: 99%

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Effect of naturally-occurring mutations on the stability and function of cancer-associated NQO1: Comparison of experiments and computation

Pacheco-García

Cagiada

Tienne-Matos

et al. 2022

Front. Mol. Biosci.

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Recent advances in DNA sequencing technologies are revealing a large individual variability of the human genome. Our capacity to establish genotype-phenotype correlations in such large-scale is, however, limited. This task is particularly challenging due to the multifunctional nature of many proteins. Here we describe an extensive analysis of the stability and function of naturally-occurring variants (found in the COSMIC and gnomAD databases) of the cancer-associated human NAD(P)H:quinone oxidoreductase 1 (NQO1). First, we performed in silico saturation mutagenesis studies (>5,000 substitutions) aimed to identify regions in NQO1 important for stability and function. We then experimentally characterized twenty-two naturally-occurring variants in terms of protein levels during bacterial expression, solubility, thermal stability, and coenzyme binding. These studies showed a good overall correlation between experimental analysis and computational predictions; also the magnitude of the effects of the substitutions are similarly distributed in variants from the COSMIC and gnomAD databases. Outliers in these experimental-computational genotype-phenotype correlations remain, and we discuss these on the grounds and limitations of our approaches. Our work represents a further step to characterize the mutational landscape of NQO1 in the human genome and may help to improve high-throughput in silico tools for genotype-phenotype correlations in this multifunctional protein associated with disease.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of naturally-occurring mutations on the stability and function of cancer-associated NQO1: Comparison of experiments and computation

Pacheco-García

Cagiada

Tienne-Matos

et al. 2022

Front. Mol. Biosci.

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Phenotypic Modulation of Cancer-Associated Antioxidant NQO1 Activity by Post-Translational Modifications and the Natural Diversity of the Human Genome

Pey

2023

Antioxidants

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Human NAD(P)H:quinone oxidoreductase 1 (hNQO1) is a multifunctional and antioxidant stress protein whose expression is controlled by the Nrf2 signaling pathway. hNQO1 dysregulation is associated with cancer and neurological disorders. Recent works have shown that its activity is also modulated by different post-translational modifications (PTMs), such as phosphorylation, acetylation and ubiquitination, and these may synergize with naturally-occurring and inactivating polymorphisms and mutations. Herein, I describe recent advances in the study of the effect of PTMs and genetic variations on the structure and function of hNQO1 and their relationship with disease development in different genetic backgrounds, as well as the physiological roles of these modifications. I pay particular attention to the long-range allosteric effects exerted by PTMs and natural variation on the multiple functions of hNQO1.

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Erratum: Conformational dynamics is key to understanding loss-of-function of NQO1 cancer-associated polymorphisms and its correction by pharmacological ligands

Abstract: In addition, the 'How to cite this article' section quoted an incorrect abbreviation for Encarnación Medina-Carmona. These errors have now been corrected in the PDF and HTML versions of the Article.

Cited by 2 publications

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Effect of naturally-occurring mutations on the stability and function of cancer-associated NQO1: Comparison of experiments and computation

Effect of naturally-occurring mutations on the stability and function of cancer-associated NQO1: Comparison of experiments and computation

Phenotypic Modulation of Cancer-Associated Antioxidant NQO1 Activity by Post-Translational Modifications and the Natural Diversity of the Human Genome

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