2016
DOI: 10.1038/srep20331
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Conformational dynamics is key to understanding loss-of-function of NQO1 cancer-associated polymorphisms and its correction by pharmacological ligands

Abstract: Protein dynamics is essential to understand protein function and stability, even though is rarely investigated as the origin of loss-of-function due to genetic variations. Here, we use biochemical, biophysical, cell and computational biology tools to study two loss-of-function and cancer-associated polymorphisms (p.R139W and p.P187S) in human NAD(P)H quinone oxidoreductase 1 (NQO1), a FAD-dependent enzyme which activates cancer pro-drugs and stabilizes several oncosuppressors. We show that p.P187S strongly des… Show more

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Cited by 41 publications
(162 citation statements)
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References 46 publications
(100 reference statements)
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“…The highly dynamic CTD of p.P187S appears to act as an efficient initiation site for its proteasomal degradation24. Consistently, removal of the CTD had significant effects on protein levels and degradation rates upon expression in an eukaryotic expression cell free system (Fig.…”
Section: Resultssupporting
confidence: 57%
See 1 more Smart Citation
“…The highly dynamic CTD of p.P187S appears to act as an efficient initiation site for its proteasomal degradation24. Consistently, removal of the CTD had significant effects on protein levels and degradation rates upon expression in an eukaryotic expression cell free system (Fig.…”
Section: Resultssupporting
confidence: 57%
“…To investigate whether CTD removal could intefere with the dynamic communication between p.P187S and the FAD binding sites, we performed MD simulations on Δ50-NQO1 variants, and analyzed their backbone dynamics using two relevant parameters24: B-factors (Fig. 7) and dihedral entropies (Figure S5).…”
Section: Resultsmentioning
confidence: 99%
“…This polymorphism shows a high frequency in human population and is significantly associated with increased cancer risk . The P187S polymorphism is known to abolish NQO1 activity by strongly decreasing FAD‐binding affinity and accelerating protein turnover by the proteasome . Intriguingly, the X‐ray crystallographic structure of P187S in the FAD‐bound (holo) state only showed subtle local rearrangements , which cannot explain the long‐range communication of its effect to the N‐terminal domain (NTD, where the FAD‐binding site is placed) or the C‐terminal domain (CTD) .…”
mentioning
confidence: 99%
“…S2) and to ensure that the proteolysis step X →F is ratelimiting, and thus, the overall proteolysis rate constant k p ≈K·k 8,41,48 . Proteolysis of GALE under native conditions is well-described by the following mechanism: N ⇔X⇒F, where X is the cleavable state in equilibrium with the native state (N), and undergoes proteolytic cleavage to produce a proteolyzed state F. The step N ↔X is governed by a equilibrium constant K, while the step X →F is determined by an intrinsic proteolysis rate constant k. To provide insight into the conformation of X, we have measured proteolysis kinetics in the presence of low urea concentrations.…”
Section: Thermodynamic Characterization Of High-energy States Under Nmentioning
confidence: 99%