Site-to-site interdomain communication may mediate different loss-of-function mechanisms in a cancer-associated NQO1 polymorphism
Por:
Medina-Carmona, E, Neira, J, Salido, E, Fuchs, J, Palomino-Morales, R, Timson, D and Pey, A
Publicada:
14 mar 2017
Categoría:
Multidisciplinary
Resumen:
Disease associated genetic variations often cause intracellular enzyme inactivation, dysregulation and instability. However, allosteric communication of mutational effects to distant functional sites leading to loss-of-function remains poorly understood. We characterize here interdomain site-to-site communication by which a common cancer-associated single nucleotide polymorphism (c.C609T/p.P187S) reduces the activity and stability in vivo of NAD(P) H: quinone oxidoreductase 1 (NQO1). NQO1 is a FAD-dependent, two-domain multifunctional stress protein acting as a Phase II enzyme, activating cancer pro-drugs and stabilizing p53 and p73 alpha oncosuppressors. We show that p. P187S causes structural and dynamic changes communicated to functional sites far from the mutated site, affecting the FAD binding site located at the N-terminal domain (NTD) and accelerating proteasomal degradation through dynamic effects on the C-terminal domain (CTD). Structural protein: protein interaction studies reveal that the cancer-associated polymorphism does not abolish the interaction with p73 alpha, indicating that oncosuppressor destabilization largely mirrors the low intracellular stability of p. P187S. In conclusion, we show how a single disease associated amino acid change may allosterically perturb several functional sites in an oligomeric and multidomain protein. These results have important implications for the understanding of loss-of-function genetic diseases and the identification of novel structural hot spots as targets for pharmacological intervention.
Filiaciones:
Medina-Carmona, E:
Univ Granada, Dept Phys Chem, Fac Sci, Ave Fuentenueva S-N, E-18071 Granada, Spain
:
Univ Miguel Hernandez, Inst Biol Mol & Celular, Avda Ferrocarril S-N, Alicante 03202, Spain
Inst Biocomp & Fis Sistemas Complejos BIFI, Zaragoza 50009, Spain
Salido, E:
Hosp Univ Canarias, Ctr Biomed Res Rare Dis CIBERER, Tenerife, Spain
Fuchs, J:
Univ Innsbruck, Inst Gen Inorgan & Theoret Chem, Fac Chem & Pharm, Innsbruck, Austria
Palomino-Morales, R:
Univ Granada, Fac Sci, Dept Biochem & Mol Biol 1, Ave Fuentenueva S-N, E-18071 Granada, Spain
Timson, D:
Univ Brighton, Sch Pharm & Biomol Sci, Brighton, E Sussex, England
Pey, A:
Univ Granada, Dept Phys Chem, Fac Sci, Ave Fuentenueva S-N, E-18071 Granada, Spain
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