Insights into the effects of cancer associated mutations at the UPF2 and ATP-binding sites of NMD master regulator: UPF1

Umesh Kalathiya , Monikaben Padariya , Kamila Pawlicka , Chandra S. Verma , Douglas Houston , Theodore Hupp , Javier Alfaro


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 eects: K164R, R253W, T499M, E637K, and E833K. To explore the eects 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.
Author Umesh Kalathiya (ICCVS)
Umesh Kalathiya,,
- International Centre for Cancer Vaccine Science
, Monikaben Padariya (ICCVS)
Monikaben Padariya,,
- International Centre for Cancer Vaccine Science
, Kamila Pawlicka
Kamila Pawlicka,,
, Chandra S. Verma
Chandra S. Verma,,
, Douglas Houston
Douglas Houston,,
, Theodore Hupp (ICCVS)
Theodore Hupp,,
- International Centre for Cancer Vaccine Science
, Javier Alfaro (ICCVS)
Javier Alfaro,,
- International Centre for Cancer Vaccine Science
Journal seriesInternational Journal of Molecular Sciences, ISSN 1422-0067, (N/A 140 pkt)
Issue year2019
Publication size in sheets1.15
Article number5644
Keywords in EnglishUPF1, ATP-binding site, UPF2, cancer mutations, structural stability, molecular dynamics simulation
ASJC Classification2700 General Medicine; 1312 Molecular Biology; 1503 Catalysis; 1604 Inorganic Chemistry; 1605 Organic Chemistry; 1606 Physical and Theoretical Chemistry; 1607 Spectroscopy; 1706 Computer Science Applications
Languageen angielski
LicenseJournal (articles only); published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)140
Score sourcejournalList
ScoreMinisterial score = 140.0, 21-02-2020, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2018 = 1.224; WoS Impact Factor: 2018 = 4.183 (2) - 2018=4.331 (5)
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