Structure of a BAG6 (Bcl-2-associated athanogene 6)-Ubl4a (ubiquitin-like protein 4a) complex reveals a novel binding interface that functions in tail-anchored protein biogenesis.
Structure of a BAG6 (Bcl-2-associated athanogene 6)-Ubl4a (ubiquitin-like protein 4a) complex reveals a novel binding interface that functions in tail-anchored protein biogenesis.
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DOI：
10.1074/jbc.m114.631804
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发表时间：
2015-04-10
期刊：
影响因子：
--
通讯作者：
Kato R
中科院分区：
文献类型：
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作者：
Kuwabara N;Minami R;Yokota N;Matsumoto H;Senda T;Kawahara H;Kato R
背景：BAG6 和 Ubl4a 都是尾锚定 (TA) 蛋白生物合成和蛋白质质量控制的介体。结果：BAG6-Ubl4a 异二聚化结构域的晶体结构揭示了独特的结合界面。结论：BAG6 的 BAG 相似结构域与其他规范的 BAG 结构域完全不同。意义：Ubl4a 与 BAG6 形成复合物，而其酵母同源物 Get5 形成同源二聚体。 BAG6 是一种必需蛋白，在两种不同的生物途径中发挥作用：泛素介导的缺陷多肽的蛋白质降解和哺乳动物中尾锚定 (TA) 跨膜蛋白的生物发生，尽管其结构和功能特性仍不清楚。我们解析了 BAG6 和 Ubl4a C 端异二聚化结构域的晶体结构，并从生化角度表征了它们的相互作用。出乎意料的是，之前被归类为 BAG 结构域的 BAG6 C 末端的特异性和结构与规范的 BAG 结构域完全不同。此外，BAG6 和 Ubl4a 的紧密结合导致细胞中 Ubl4a 蛋白稳定性的调节。因此，我们建议将 BAG6 的 Ubl4a 结合区指定为新的 BAG 类似 (BAGS) 结构域。与 BAG6 相互作用的 Ubl4a 的结构类似于酵母同源物 Get5，形成同源二聚体。这些观察结果表明，BAG6 的 BAGS 结构域通过与 Ubl4a 相互作用促进哺乳动物中 TA 蛋白生物发生途径。
Background: Both BAG6 and Ubl4a are mediators of tail-anchored (TA) protein biogenesis and protein quality control. Results: The crystal structure of the BAG6-Ubl4a heterodimerization domain reveals a unique binding interface. Conclusion: The BAG-similar domain of BAG6 is completely distinct from other canonical BAG domains. Significance: Ubl4a forms a complex with BAG6, whereas its yeast homologue Get5 forms a homodimer. BAG6 is an essential protein that functions in two distinct biological pathways, ubiquitin-mediated protein degradation of defective polypeptides and tail-anchored (TA) transmembrane protein biogenesis in mammals, although its structural and functional properties remain unknown. We solved a crystal structure of the C-terminal heterodimerization domains of BAG6 and Ubl4a and characterized their interaction biochemically. Unexpectedly, the specificity and structure of the C terminus of BAG6, which was previously classified as a BAG domain, were completely distinct from those of the canonical BAG domain. Furthermore, the tight association of BAG6 and Ubl4a resulted in modulation of Ubl4a protein stability in cells. Therefore, we propose to designate the Ubl4a-binding region of BAG6 as the novel BAG-similar (BAGS) domain. The structure of Ubl4a, which interacts with BAG6, is similar to the yeast homologue Get5, which forms a homodimer. These observations indicate that the BAGS domain of BAG6 promotes the TA protein biogenesis pathway in mammals by the interaction with Ubl4a.