Institute of Structural Biology, Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Josef-Schneider-Straße 2, 97080, Würzburg, Germany.
Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, 33612, USA.
Nat Commun. 2022 Aug 15;13(1):4789. doi: 10.1038/s41467-022-32040-6.
The covalent modification of target proteins with ubiquitin or ubiquitin-like modifiers is initiated by E1 activating enzymes, which typically transfer a single modifier onto cognate conjugating enzymes. UBA6 is an unusual E1 since it activates two highly distinct modifiers, ubiquitin and FAT10. Here, we report crystal structures of UBA6 in complex with either ATP or FAT10. In the UBA6-FAT10 complex, the C-terminal domain of FAT10 binds to where ubiquitin resides in the UBA1-ubiquitin complex, however, a switch element ensures the alternate recruitment of either modifier. Simultaneously, the N-terminal domain of FAT10 interacts with the 3-helix bundle of UBA6. Site-directed mutagenesis identifies residues permitting the selective activation of either ubiquitin or FAT10. These results pave the way for studies investigating the activation of either modifier by UBA6 in physiological and pathophysiological settings.
泛素或泛素样修饰物与靶蛋白的共价修饰是由 E1 激活酶启动的，这些酶通常将单个修饰物转移到同源连接酶上。UBA6 是一种不寻常的 E1，因为它可以激活两种高度不同的修饰物，即泛素和 FAT10。在这里，我们报告了 UBA6 分别与 ATP 或 FAT10 形成复合物的晶体结构。在 UBA6-FAT10 复合物中，FAT10 的 C 末端结构域与 UBA1-泛素复合物中泛素的位置结合，但一个开关元件确保了两种修饰物的交替招募。同时，FAT10 的 N 末端结构域与 UBA6 的 3 螺旋束相互作用。定点突变鉴定出允许选择性激活泛素或 FAT10 的残基。这些结果为研究 UBA6 在生理和病理生理条件下激活两种修饰物的研究铺平了道路。
