Furuhata Takafumi, Choi Bumkyu, Uno Taiki, Shinohara Ryota, Sato Yusuke, Okatsu Kei, Fukai Shuya, Okamoto Akimitsu
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101, Koyama-cho Minami, Tottori 680-8552, Japan.
J Am Chem Soc. 2024 Oct 3. doi: 10.1021/jacs.4c11279.
The multimerization of ubiquitins at different positions of lysine residues to form heterotypic polyubiquitin chains is a post-translational modification that is essential for the precise regulation of protein functions and degradative fates in living cells. The understanding of structure-activity relationships underlying their diverse properties has been seriously impeded by difficulties in the preparation of a series of folded heterotypic chains appropriately functionalized with different chemical tags for the systematic evaluation of their multifaceted functions. Here, we report a chemical diversification of enzymatically assembled polyubiquitin chains that enables the facile preparation of folded heterotypic chains with different functionalities. By introducing an acyl hydrazide at the C terminus of the proximal ubiquitin, polyubiquitin chains were readily diversified from the same starting materials with a variety of molecules, ranging from small molecules to biopolymers, under nondenaturing conditions. This chemical diversification allowed the systematic study of the functional differences of K63/K48 heterotypic chains based on the position of the branch point during enzymatic deubiquitination and proteasomal proteolysis, thus demonstrating critical roles of the branch position in both the positive and negative control of ubiquitin-mediated reactions. The chemical diversification of the heterotypic chains provides a robust chemical platform to reframe the understanding of how the ubiquitin codes are regulated from the viewpoint of the branch structure for the precise control of cell functions, which has not been deciphered solely on the basis of the linkage types.
泛素在赖氨酸残基的不同位置多聚化形成异型多聚泛素链,这是一种翻译后修饰,对于活细胞中蛋白质功能和降解命运的精确调控至关重要。由于难以制备一系列用不同化学标签适当功能化的折叠异型链以系统评估其多方面功能,对其多样性质背后的构效关系的理解受到严重阻碍。在此,我们报道了酶促组装的多聚泛素链的化学多样化,它能够轻松制备具有不同功能的折叠异型链。通过在近端泛素的C末端引入酰肼,在非变性条件下,多聚泛素链很容易从相同的起始材料与各种分子(从小分子到生物聚合物)多样化。这种化学多样化使得基于酶促去泛素化和蛋白酶体蛋白水解过程中分支点的位置对K63/K48异型链的功能差异进行系统研究成为可能,从而证明了分支位置在泛素介导反应的正负调控中的关键作用。异型链的化学多样化提供了一个强大的化学平台,从分支结构的角度重新构建对泛素编码如何被调控以精确控制细胞功能的理解,而这仅基于连接类型是无法解读的。