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

Chandra S. Verma¹  Kamila Pawlicka²  Douglas Houston³  Umesh Kalathiya⁴  Monikaben Padariya⁴  Javier Antonio Alfaro⁴  Ted R. Hupp⁴ 

[1] Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, 07-01 Matrix, Singapore 138671, Singapore;University of Edinburgh, Institute of Genetics and Molecular Medicine, Edinburgh, Scotland EH4 2XR, UK;University of Edinburgh, Institute of Quantitative Biology, Biochemistry and Biotechnology, Edinburgh, Scotland EH9 3BF, UK;University of Gdansk, International Centre for Cancer Vaccine Science, Wita Stwosza 63, 80-308 Gdansk, Poland;

关键词: upf1;    atp-binding site;    upf2;    cancer mutations;    structural stability;    molecular dynamics simulations;   

DOI  :  10.3390/ijms20225644

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown