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, Ted Hupp, Javier Antonio Alfaro

Research output: Contribution to journalArticlepeer-review

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 theCH-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.
Original languageEnglish
JournalInternational Journal of Molecular Sciences
DOIs
Publication statusPublished - 11 Nov 2019

Keywords

  • UPF1
  • ATP-binding site
  • UPF2
  • cancer mutations
  • structural stability
  • molecular dynamics simulations

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