Protein quality control (PQC) degrons are short protein segments that target misfolded proteins for proteasomal degradation, and thus protect cells against the accumulation of potentially toxic non-native proteins. Studies have shown that PQC degrons are hydrophobic and rarely contain negatively charged residues, features which are shared with chaperone-binding regions. Here we explore the notion that chaperone-binding regions may function as PQC degrons. When directly tested, we found that a canonical Hsp70-binding motif (the APPY peptide) functioned as a dose-dependent PQC degron both in yeast and in human cells. In yeast, Hsp70, Hsp110, Fes1, and the E3 Ubr1 target the APPY degron. Screening revealed that the sequence space within the chaperone-binding region of APPY that is compatible with degron function is vast. We find that the number of exposed Hsp70-binding sites in the yeast proteome correlates with a reduced protein abundance and half-life. Our results suggest that when protein folding fails, chaperone-binding sites may operate as PQC degrons, and PQC-linked degradation therefore overlaps in specificity with chaperone binding. This sheds new light on how the PQC system has evolved to exploit the intrinsic capacity of chaperones to recognize misfolded proteins, thereby placing them at the nexus of protein folding and degradation.

中文翻译：

---

HSP70 结合基序作为蛋白质质量控​​制 degrons

蛋白质质量控​​制 (PQC) degrons 是短蛋白质片段，靶向错误折叠的蛋白质以进行蛋白酶体降解，从而保护细胞免受潜在毒性非天然蛋白质的积累。研究表明，PQC degrons 是疏水性的，很少含有带负电荷的残基，这些特征与伴侣结合区域共有。在这里，我们探讨了伴侣结合区域可能作为 PQC degrons 发挥作用的概念。直接测试时，我们发现典型的 Hsp70 结合基序（APPY 肽）在酵母和人类细胞中都起着剂量依赖性 PQC 降解决定子的作用。在酵母中，Hsp70、Hsp110、Fes1 和 E3 Ubr1 靶向 APPY degron。筛选显示 APPY 的伴侣结合区内与 degron 功能相容的序列空间是巨大的。我们发现酵母蛋白质组中暴露的 Hsp70 结合位点的数量与减少的蛋白质丰度和半衰期相关。我们的结果表明，当蛋白质折叠失败时，分子伴侣结合位点可能作为 PQC 降解子起作用，因此 PQC 相关降解在特异性上与分子伴侣结合重叠。这揭示了 PQC 系统如何进化以利用分子伴侣识别错误折叠蛋白质的内在能力，从而将它们置于蛋白质折叠和降解的联系中。