Molecular basis of neurodevelopmental disorder-causing mutation in nonsense-mediated mRNA decay factor UPF3B

Abstract

UPF3B is a key nonsense-mediated mRNA decay (NMD) factor required for surveillance of mRNA and regulation of eukaryotic gene expression. Mutations in UPF3B cause intellectual disability. The underlying molecular mechanisms remain unexplored as the mutations lie in an uncharacterized region of UPF3B. Here, we show that UPF3B shares structural and functional homology to the Drosophila Behavior/Human Splicing protein family comprising an RNA-recognition motif-like domain (RRM-L), a NONA/paraspeckle-like domain (NOPS-L), and extended α-helical domains essential for ribosome- and RNA-binding and RNA-induced oligomerization. A co-crystal structure of UPF3B with the third middle domain of eukaryotic initiation factor 4G (MIF4GIII) of UPF2 reveals an unexpectedly intimate binding interface.