(A) Surface rendering of the SMG5 (green) and SMG6 (purple) PIN domains. The interaction surfaces (upper part) and the complex (lower part) of both PIN domains are depicted. The catalytic center of the composite endonuclease is indicated by the positions of the RNA, the conserved aspartates, and the two Mn2+ cations (courtesy of Stefanie Jonas). (B) Revised working model for metazoan NMD (adapted from Karousis and Muhlemann 2022). Translation termination at a premature termination codon (PTC) triggers SMG1-mediated hyperphosphorylation of UPF1, facilitated by UPF2, UPF3B, and the EJC (activation step). Hyperphosphorylated UPF1 recruits SMG6 and SMG5:SMG7 to the RNA, allowing assembly of the composite SMG5–SMG6 PIN endonuclease, which cleaves the target mRNA.
