CAT-tailing as a fail-safe mechanism for efficient degradation of stalled nascent polypeptides

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Science  28 Jul 2017:
Vol. 357, Issue 6349, pp. 414-417
DOI: 10.1126/science.aam7787

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A tale of CAT tails

When protein translation fails, the incomplete nascent polypeptide is targeted for degradation by the highly conserved ribosome-associated quality control complex (RQC). Mutations in RQC components lead to stress at the cellular level and neurodegeneration at the organismal level. Recent studies have shown that RQC tags partially synthesize proteins with C-terminal alanine and threonine (CAT) tails in an unusual elongation reaction. Working in yeast, Kostova et al. elucidated the role of this process. CAT-tailing is a fail-safe mechanism to ensure the degradation of partially synthesized proteins. The elongation process appears to “push” lysines out of the ribosome exit tunnel, which allows them to be marked by ubiquitin degradation signals.

Science, this issue p. 414


Ribosome stalling leads to recruitment of the ribosome quality control complex (RQC), which targets the partially synthesized polypeptide for proteasomal degradation through the action of the ubiquitin ligase Ltn1p. A second core RQC component, Rqc2p, modifies the nascent polypeptide by adding a carboxyl-terminal alanine and threonine (CAT) tail through a noncanonical elongation reaction. Here we examined the role of CAT-tailing in nascent-chain degradation in budding yeast. We found that Ltn1p efficiently accessed only nascent-chain lysines immediately proximal to the ribosome exit tunnel. For substrates without Ltn1p-accessible lysines, CAT-tailing enabled degradation by exposing lysines sequestered in the ribosome exit tunnel. Thus, CAT-tails do not serve as a degron, but rather provide a fail-safe mechanism that expands the range of RQC-degradable substrates.

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