000060977 001__ 60977
000060977 005__ 20190819101353.0
000060977 0247_ $$2doi$$a10.1038/srep44532
000060977 0248_ $$2sideral$$a98547
000060977 037__ $$aART-2017-98547
000060977 041__ $$aeng
000060977 100__ $$aMedina-Carmona, E.
000060977 245__ $$aSite-to-site interdomain communication may mediate different loss-of-function mechanisms in a cancer-associated NQO1 polymorphism
000060977 260__ $$c2017
000060977 5060_ $$aAccess copy available to the general public$$fUnrestricted
000060977 5203_ $$aDisease 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.
000060977 536__ $$9info:eu-repo/grantAgreement/ES/MINECO/BIO2015-66426-R$$9info:eu-repo/grantAgreement/ES/MINECO/CTQ2015-64445-R$$9info:eu-repo/grantAgreement/ES/MINECO/SAF2015-69796
000060977 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000060977 590__ $$a4.122$$b2017
000060977 591__ $$aMULTIDISCIPLINARY SCIENCES$$b12 / 64 = 0.188$$c2017$$dQ1$$eT1
000060977 592__ $$a1.533$$b2017
000060977 593__ $$aMultidisciplinary$$c2017$$dQ1
000060977 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000060977 700__ $$0(orcid)0000-0003-0668-977X$$aNeira, J. L.$$uUniversidad de Zaragoza
000060977 700__ $$aSalido, E.
000060977 700__ $$aFuchs, J. E.
000060977 700__ $$aPalomino-Morales, R.
000060977 700__ $$aTimson, D. J.
000060977 700__ $$aPey, A. L.
000060977 7102_ $$15007$$2570$$aUniversidad de Zaragoza$$bDpto. Informát.Ingenie.Sistms.$$cÁrea Lenguajes y Sistemas Inf.
000060977 773__ $$g7 (2017), 44532 [18 pp.]$$pSci. rep.$$tScientific reports$$x2045-2322
000060977 8564_ $$s3445519$$uhttps://zaguan.unizar.es/record/60977/files/texto_completo.pdf$$yVersión publicada
000060977 8564_ $$s107517$$uhttps://zaguan.unizar.es/record/60977/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000060977 909CO $$ooai:zaguan.unizar.es:60977$$particulos$$pdriver
000060977 951__ $$a2019-08-19-09:51:27
000060977 980__ $$aARTICLE