Mechanism and evolutionary origins of alanine-tail C-degron recognition by E3 ligases Pirh2 and CRL2-KLHDC10.
Mechanism and evolutionary origins of alanine-tail C-degron recognition by E3 ligases Pirh2 and CRL2-KLHDC10.
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DOI：
10.1016/j.celrep.2023.113100
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发表时间：
2023-09-26
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影响因子：
8.8
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中科院分区：
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在核糖体相关质量控制（RQC）中，通过中断翻译产生的新生多肽用C-末端聚丙氨酸尾（“Ala-尾”）修饰，所述C-末端聚丙氨酸尾在核糖体外部起作用以通过E3连接酶Pirh 2（含有p53诱导的RING-H2结构域）或CRL 2（Cullin-2 RING连接酶2）-KLHDC 10诱导泛素化。在这里，我们调查的丙氨酸尾功能的分子基础，使用生物化学和计算机模拟的方法。我们发现，Pirh 2和KLHDC 10直接绑定到丙氨酸-尾巴和结构预测确定候选人丙氨酸-尾巴结合位点，我们的实验验证。涉及Ala尾识别的degron结合口袋和特定口袋残基在Pirh 2和KLHDC 10同源物中是保守的，这表明这些连接酶在真核生物中的重要功能是靶向Ala尾底物。此外，我们确定，这两个丙氨酸尾结合口袋已经收敛进化，无论是从一个古老的模块的细菌来源（Pirh 2）或通过修补一个广泛的C-降解决定子识别元件（KLHDC 10）。这些结果揭示了一个简单的降解决定子序列的识别和Ala尾蛋白水解信号的进化。核糖体相关质量控制（RQC）通过C-末端丙氨酸尾降解决定子修饰核糖体失速产生的不完整多肽。在人类中，丙氨酸尾（Ala尾）蛋白被E3连接酶Pirh 2和CRL 2-KLHDC 10泛素化，但如何感知Ala尾仍不清楚。Patil等人为Ala尾识别提供了结构基础，并深入了解了其进化。
In ribosome-associated quality control (RQC), nascent polypeptides produced by interrupted translation are modified with C-terminal polyalanine tails (“Ala-tails”) that function outside ribosomes to induce ubiquitylation by E3 ligases Pirh2 (p53-induced RING-H2 domain-containing) or CRL2 (Cullin-2 RING ligase2)-KLHDC10. Here, we investigate the molecular basis of Ala-tail function using biochemical and in silico approaches. We show that Pirh2 and KLHDC10 directly bind to Ala-tails and that structural predictions identify candidate Ala-tail-binding sites, which we experimentally validate. The degron-binding pockets and specific pocket residues implicated in Ala-tail recognition are conserved among Pirh2 and KLHDC10 homologs, suggesting that an important function of these ligases across eukaryotes is in targeting Ala-tailed substrates. Moreover, we establish that the two Ala-tail-binding pockets have convergently evolved, either from an ancient module of bacterial provenance (Pirh2) or via tinkering of a widespread C-degron-recognition element (KLHDC10). These results shed light on the recognition of a simple degron sequence and the evolution of Ala-tail proteolytic signaling. Ribosome-associated quality control (RQC) modifies incomplete polypeptides produced by ribosomal stalling with C-terminal alanine-tail degrons. In humans, alanine-tailed (Ala-tailed) proteins are ubiquitylated by E3 ligases Pirh2 and CRL2-KLHDC10, but how Ala-tails are sensed remained unclear. Patil et al. provide a structural basis for Ala-tail recognition and insights into its evolution.
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影响因子：
16
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影响因子：
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