A mechanism for cancer-associated inactivation of NQO1 due to P187S and its reactivation by the consensus mutation H80R

DOI: 10.1002/1873-3468.12772

Authors: Ines G. Munoz (Spanish National Cancer Research Centre (CNIO)) , Bertrand Morel (University of Granada) , Encarnación Medina-Carmona (University of Granada) , Angel L. Pey (University of Granada)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Febs Letters

State: Published (Approved)
Published: August 2017
Diamond Proposal Number(s): 12571

Abstract: The cancer-associated P187S polymorphism in the NAD(P)H:quinone oxidoreductase 1 (NQO1) abolishes enzyme activity by strongly reducing FAD binding affinity. A single mammalian consensus mutation (H80R) protects P187S from inactivation. To provide mechanistic insight into these effects, we report here a detailed structural and thermodynamic characterization of FAD binding to these NQO1 variants. Our results show that H80R causes a population shift in the conformational ensemble of apo-P187S, remodeling the structure and dynamics of the FAD binding site and reducing the energetic penalization arising from the equilibrium between apo- and holo-states. Our analyses illustrate how single amino acid changes can profoundly affect structural and mechanistic features of protein functional traits, with implications for our understanding of protein evolution and human disease.

Journal Keywords: FAD binding thermodynamics; structure-energetics relationships; mutations in disease and evolution

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Medicine


Instruments: B21-High Throughput SAXS

Added On: 17/08/2017 15:12

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)