期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 30, 期 9, 页码 1314-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41594-023-01075-8
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This study demonstrates that mammalian CCR4-NOT can specifically recognize stalled ribosomes and stabilize the interaction through protein-protein interactions. The findings suggest that human CCR4-NOT not only detects ribosomal stalling but also links translation to mRNA decay through a specific signaling pathway.
Translation affects messenger RNA stability and, in yeast, this is mediated by the Ccr4-Not deadenylation complex. The details of this process in mammals remain unclear. Here, we use cryogenic electron microscopy (cryo-EM) and crosslinking mass spectrometry to show that mammalian CCR4-NOT specifically recognizes ribosomes that are stalled during translation elongation in an in vitro reconstituted system with rabbit and human components. Similar to yeast, mammalian CCR4-NOT inserts a helical bundle of its CNOT3 subunit into the empty E site of the ribosome. Our cryo-EM structure shows that CNOT3 also locks the L1 stalk in an open conformation to inhibit further translation. CCR4-NOT is required for stable association of the nonconstitutive subunit CNOT4, which ubiquitinates the ribosome, likely to signal stalled translation elongation. Overall, our work shows that human CCR4-NOT not only detects but also enforces ribosomal stalling to couple translation and mRNA decay.
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