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Title: Insights into the effects of cancer associated mutations at the UPF2 and ATP-binding sites of NMD master regulator : UPF1
Authors: Kalathiya, Umesh
Padariya, Monikaben
Pawlicka, Kamila
Verma, Chandra Shekhar
Houston, Douglas
Hupp, Ted R.
Alfaro, Javier Antonio
Keywords: Science::Biological sciences
Issue Date: 2019
Source: Kalathiya, 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/ijms20225644
Journal: International Journal of Molecular Sciences
Abstract: Nonsense-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.
ISSN: 1661-6596
DOI: 10.3390/ijms20225644
Schools: School of Biological Sciences 
Organisations: Bioinformatics Institute, A*STAR
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 (
Fulltext Permission: open
Fulltext Availability: With Fulltext
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