Kuwabara Naoyuki, Minami Ryosuke, Yokota Naoto, Matsumoto Hirofumi, Senda Toshiya, Kawahara Hiroyuki, Kato Ryuichi
From the Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), 1-1 Oho, Tsukuba, Ibaraki 305-0801, Japan and.
the Department of Biological Sciences, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo 192-0397, Japan.
J Biol Chem. 2015 Apr 10;290(15):9387-98. doi: 10.1074/jbc.M114.631804. Epub 2015 Feb 20.
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.
BAG6是一种必需蛋白，在哺乳动物中参与两种不同的生物学途径，即泛素介导的缺陷多肽蛋白降解和尾锚定（TA）跨膜蛋白生物合成，尽管其结构和功能特性尚不清楚。我们解析了BAG6和Ubl4a C端异源二聚化结构域的晶体结构，并对它们的相互作用进行了生化表征。出乎意料的是，先前被归类为BAG结构域的BAG6 C端的特异性和结构与典型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与Ubl4a结合的区域命名为新型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，后者形成同二聚体。这些观察结果表明，BAG6的BAGS结构域通过与Ubl4a的相互作用促进哺乳动物中的TA蛋白生物合成途径。
