Programmed Protein Self-Assembly Driven by Genetically Encoded Intein-Mediated Native Chemical Ligation

ACS Synthetic Biology
Joseph A HarveyEwan R G Main

Abstract

Harnessing and controlling self-assembly is an important step in developing proteins as novel biomaterials. With this goal, here we report the design of a general genetically programmed system that covalently concatenates multiple distinct protein domains into specific assembled arrays. It is driven by iterative intein-mediated native chemical ligation (NCL) under mild native conditions. The system uses a series of initially inert recombinant protein fusions that sandwich the protein modules to be ligated between one of a number of different affinity tags and an intein protein domain. Orthogonal activation at opposite termini of compatible protein fusions, via protease and intein cleavage, coupled with sequential mixing directs an irreversible and traceless stepwise assembly process. This gives total control over the composition and arrangement of component proteins within the final product, enabled the limits of the system-reaction efficiency and yield-to be investigated, and led to the production of "functional" assemblies.

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Citations

Oct 23, 2018·Protein Science : a Publication of the Protein Society·Stephen B H Kent
Mar 16, 2021·Current Opinion in Structural Biology·Frances Gidley, Fabio Parmeggiani
May 4, 2018·Journal of the American Chemical Society·Justin A ModicaMilan Mrksich

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