Institute for Complex Molecular Systems and, Laboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, P.O. Box 513, 5600, MB, Eindhoven, The Netherlands.
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita 565-0871, Osaka, Japan.
Angew Chem Int Ed Engl. 2021 May 10;60(20):11262-11266. doi: 10.1002/anie.202102160. Epub 2021 Apr 8.
Hexameric hemoprotein (HTHP) is employed as a scaffold protein for the supramolecular assembly and activation of the apoptotic signalling enzyme caspase-9, using short DNA elements as modular recruitment domains. Caspase-9 assembly and activation on the HTHP platform due to enhanced proximity is followed by combinatorial inhibition at high scaffold concentrations. The DNA recruitment domains allow for reversible switching of the caspase-9 assembly and activity state using short modulatory DNA strands. Tuning of the recruitment domain affinity allows for generating kinetically trapped active enzyme complexes, as well as for dynamic repositioning of caspases over scaffold populations and inhibition using monovalent sink platforms. The conceptual combination of a highly structured multivalent protein platform with modular DNA recruitment domains provides emergent biomimicry properties with advanced levels of control over protein assembly.
六聚体血红素蛋白 (HTHP) 被用作超分子组装和凋亡信号酶 caspase-9 的激活的支架蛋白，使用短 DNA 元件作为模块化招募结构域。由于增强的邻近性，HTHP 平台上的 caspase-9 组装和激活导致在高支架浓度下进行组合抑制。DNA 招募结构域允许使用短的调节 DNA 链可逆地切换 caspase-9 的组装和活性状态。通过调整招募结构域的亲和力，可以产生动力学捕获的活性酶复合物，以及通过单价陷闭平台在支架群体上动态重新定位和抑制 caspase。高度结构化的多价蛋白平台与模块化 DNA 招募结构域的概念组合提供了新兴的仿生特性，并对蛋白组装进行了高级别的控制。
