UPF1 ATPase autoinhibition and activation modulate RNA binding kinetics and NMD efficiency

• DOI: 10.1101/2023.11.03.565554
• Publication Date: 2023-11-04T03:55:18Z
• Authors: Joseph H. Chapman; Alice M. Youle; Acadia L. Grimme; Keir C. Neuman; J. Robert Hogg
• Keywords: Nonsense-Mediated Decay

Abstract The RNA helicase UPF1 interacts with mRNAs, mRNA decay machinery, and the terminating ribosome to promote nonsense-mediated (NMD). Structural biochemical data have revealed that exists in an enzymatically autoinhibited “closed” state. Upon binding NMD protein UPF2, undergoes extensive conformational change into a more active “open” state, which exhibits enhanced ATPase activity. However, mechanically deficient mutants can support efficient NMD, bringing question roles of enzymatic autoinhibition activation NMD. Here, we identify two additional important features activated open state: slower nucleic acid kinetics ATP-stimulated dissociation kinetics. Computational modeling based on empirical measurements UPF1, interaction predicts majority UPF1-RNA events cells occur independently UPF2 binding. We find either reduced or accelerated from defects, whereas are dependent for catalytic activity remain well-established targets. These findings model UPF1-mRNA interactions determinants cellular efficiency.