Please use this identifier to cite or link to this item: https://doi.org/10.3390/ijms20225644
Title: Insights into the effects of cancer associated mutations at the upf2 and atp-binding sites of nmd master regulator: Upf1
Authors: Kalathiya, U.
Padariya, M.
Pawlicka, K.
Verma, C.S. 
Houston, D.
Hupp, T.R.
Alfaro, J.A.
Keywords: ATP-binding site
Cancer mutations
Molecular dynamics simulations
Structural stability
UPF1
UPF2
Issue Date: 2019
Publisher: MDPI AG
Citation: 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. ScholarBank@NUS Repository. https://doi.org/10.3390/ijms20225644
Rights: Attribution 4.0 International
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. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
Source Title: International Journal of Molecular Sciences
URI: https://scholarbank.nus.edu.sg/handle/10635/209919
ISSN: 1661-6596
DOI: 10.3390/ijms20225644
Rights: Attribution 4.0 International
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