Instructed Assembly of Peptides for Intracellular Enzyme Sequestration

Journal of the American Chemical Society
Zhaoqianqi FengBing Xu

Abstract

Liquid-like droplets of biomacromolecules are emerging as a fundamental mechanism of cellular signaling, but designing synthetic mimics to form such membraneless organelles remains unexplored. Here we report the use of supramolecular assemblies of small peptides, as a mimic of biomacromolecular condensates, for intracellular sequestration of enzymes on endoplasmic reticulum (ER). Specifically, integrating a short peptide with naproxen (a nonsteroidal anti-inflammatory drug (NSAID) and a ligand of cyclooxygenase-2 (COX-2)) generates an enzymatic substrate that acts as a precursor for instructed assembly. Slowly dephosphorylating the precursors by phosphatases forms the corresponding hydrogelators in a cellular environment, which results in the supramolecular assemblies on ER. Consisting of the precursor and the hydrogelator molecules, the assemblies enable the sequestration of COX-2 and protein-tyrosine phosphatase 1B (PTP1B) on ER. Further structure-activity investigation reveals that the colocalization of COX-2 and PTP1B relies on the NSAID motif, the phosphotyrosine, and the enzymatic dephosphorylation of the precursor. This work, for the first time, illustrates the use of supramolecular processes for associating enzymes in c...Continue Reading

Citations

Mar 25, 2019·Angewandte Chemie·Huaimin WangBing Xu
Mar 25, 2020·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Biyun SunAdam D Martin
Apr 9, 2019·Chembiochem : a European Journal of Chemical Biology·Huaimin WangBing Xu
Sep 12, 2019·Biomaterials Science·Qian WangJianfeng Liu
Dec 24, 2018·Nature Methods·Lei Tang
Jan 13, 2021·Biomaterials Science·Jonathan DoroginMarian H Hettiaratchi
Aug 20, 2020·Chemical Reviews·Hongjian HeBing Xu
Jun 9, 2021·Nature Communications·Takayuki MikiHisakazu Mihara

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