Site-to-site interdomain communication may mediate different loss-of-function mechanisms in a cancer-associated NQO1 polymorphism

Medina-Carmona, E. ; Neira, J. L. (Universidad de Zaragoza) ; Salido, E. ; Fuchs, J. E. ; Palomino-Morales, R. ; Timson, D. J. ; Pey, A. L.

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 p73a 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 p73a, 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.

Idioma: Inglés

DOI: 10.1038/srep44532

Año: 2017

Publicado en: Scientific reports 7 (2017), 44532 [18 pp.]
ISSN: 2045-2322

Factor impacto JCR: 4.122 (2017)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 12 / 64 = 0.188 (2017) - Q1 - T1

Factor impacto SCIMAGO: 1.533 - Multidisciplinary (Q1)

Financiación: info:eu-repo/grantAgreement/ES/MINECO/BIO2015-66426-R
Financiación: info:eu-repo/grantAgreement/ES/MINECO/CTQ2015-64445-R
Financiación: info:eu-repo/grantAgreement/ES/MINECO/SAF2015-69796

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Lenguajes y Sistemas Inf. (Dpto. Informát.Ingenie.Sistms.)