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Dynamic Protease Activation on a Multimeric Synthetic Protein Scaffold via Adaptable DNA‐Based Recruitment Domains
Author(s) -
Mashima Tsuyoshi,
Rosier Bas J. H. M.,
Oohora Koji,
Greef Tom F. A.,
Hayashi Takashi,
Brunsveld Luc
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202102160
Subject(s) - scaffold , scaffold protein , dna , supramolecular chemistry , dna nanotechnology , microbiology and biotechnology , protease , modular design , synthetic biology , chemistry , biophysics , caspase , enzyme , nanotechnology , biochemistry , biology , apoptosis , signal transduction , computational biology , materials science , computer science , programmed cell death , crystallography , database , crystal structure , operating system
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.