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. Author manuscript; available in PMC: 2023 Sep 13.
Published in final edited form as: Nat Struct Mol Biol. 2023 Aug 31;30(9):1314–1322. doi: 10.1038/s41594-023-01075-8

Fig. 6. Model for CCR4-NOT and CNOT4 recognition of mammalian ribosomes during slow elongation.

Fig. 6

Elongating ribosomes in the canonical state with peptidyl-tRNA (green) in the P site and deacylated tRNA (gold) in the E site await the next cognate aminoacyl-tRNA (purple) (top, left). Various aminoacyl-tRNA•eEF1A•GTP ternary complexes sample the A site codon during decoding until the cognate aminoacyl-tRNA arrives and accommodates upon GTP hydrolysis and egress of eEF1A (top). Peptidyl transfer to lengthen the nascent chain (hollow red beads) by one residue (solid red bead), subunit rotation and formation of hybrid state A/P and P/E tRNAs occur spontaneously. eEF2•GTP is recruited to this state and uses GTP hydrolysis to mediate translocation by advancing the mRNA by one codon to reset the cycle to the next post-translocation state. If the next cognate tRNA is slow to arrive (bottom), the post-translocation state persists, and the E-site tRNA leaves. CCR4-NOT and CNOT4 bind these ribosomes and mono-ubiquitinate eS7. It remains unclear whether CNOT4 recruits CCR4-NOT or vice versa. Binding reinforces translational stalling and may trigger poly(A) tail removal, decapping and mRNA decay by CCR4-NOT exonucleases. Crosslinking mass spectrometry data suggest a close proximity between CNOT6 and CNOT3 NTR, CNOT10/11 module and CNOT3 NTR, and the 40S and the CNOT10/11 module. These interactions are depicted in cis using dotted arrows, although we cannot exclude other models or geometries.