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dc.contributor.authorKalathiya, Umeshen_US
dc.contributor.authorPadariya, Monikabenen_US
dc.contributor.authorPawlicka, Kamilaen_US
dc.contributor.authorVerma, Chandra Shekharen_US
dc.contributor.authorHouston, Douglasen_US
dc.contributor.authorHupp, Ted R.en_US
dc.contributor.authorAlfaro, Javier Antonioen_US
dc.identifier.citationKalathiya, U., Padariya, M., Pawlicka, K., Verma, C. S., Houston, D., Hupp, T. R., & Alfaro, J. A. (2019). Insights into the effects of cancer associated mutations at the UPF2 and ATP-binding sites of NMD master regulator : UPF1. International Journal of Molecular Sciences, 20(22), 5644-. doi:10.3390/ijms20225644en_US
dc.description.abstractNonsense-mediated mRNA decay (NMD) is a quality control mechanism that recognizes post-transcriptionally abnormal transcripts and mediates their degradation. The master regulator of NMD is UPF1, an enzyme with intrinsic ATPase and helicase activities. The cancer genomic sequencing data has identified frequently mutated residues in the CH-domain and ATP-binding site of UPF1. In silico screening of UPF1 stability change as a function over 41 cancer mutations has identified five variants with significant effects: K164R, R253W, T499M, E637K, and E833K. To explore the effects of these mutations on the associated energy landscape of UPF1, molecular dynamics simulations (MDS) were performed. MDS identified stable H-bonds between residues S152, S203, S205, Q230/R703, and UPF2/AMPPNP, and suggest that phosphorylation of Serine residues may control UPF1-UPF2 binding. Moreover, the alleles K164R and R253W in the CH-domain improved UPF1-UPF2 binding. In addition, E637K and E833K alleles exhibited improved UPF1-AMPPNP binding compared to the T499M variant; the lower binding is predicted from hindrance caused by the side-chain of T499M to the docking of the tri-phosphate moiety (AMPPNP) into the substrate site. The dynamics of wild-type/mutant systems highlights the flexible nature of the ATP-binding region in UPF1. These insights can facilitate the development of drug discovery strategies for manipulating NMD signaling in cell systems using chemical tools.en_US
dc.relation.ispartofInternational Journal of Molecular Sciencesen_US
dc.rights© 2019 The Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (
dc.subjectScience::Biological sciencesen_US
dc.titleInsights into the effects of cancer associated mutations at the UPF2 and ATP-binding sites of NMD master regulator : UPF1en_US
dc.typeJournal Articleen
dc.contributor.schoolSchool of Biological Sciencesen_US
dc.contributor.organizationBioinformatics Institute, A*STARen_US
dc.description.versionPublished versionen_US
dc.subject.keywordsATP-binding Siteen_US
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