Kostova Kamena K, Hickey Kelsey L, Osuna Beatriz A, Hussmann Jeffrey A, Frost Adam, Weinberg David E, Weissman Jonathan S
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Science. 2017 Jul 28;357(6349):414-417. doi: 10.1126/science.aam7787.
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.
核糖体停滞会导致核糖体质量控制复合体（RQC）的募集，该复合体通过泛素连接酶Ltn1p的作用，将部分合成的多肽靶向蛋白酶体降解。RQC的第二个核心组分Rqc2p通过非经典延伸反应，在新生多肽的羧基末端添加丙氨酸和苏氨酸（CAT）尾巴，从而对新生多肽进行修饰。在此，我们研究了CAT尾巴化在芽殖酵母新生链降解中的作用。我们发现，Ltn1p仅能有效地作用于紧邻核糖体出口通道的新生链赖氨酸。对于没有Ltn1p可作用赖氨酸的底物，CAT尾巴化通过暴露隐藏在核糖体出口通道中的赖氨酸来实现降解。因此，CAT尾巴不是一种降解结构域，而是提供了一种故障安全机制，扩大了RQC可降解底物的范围。
