Dataset Information

Instructed Assembly of Peptides for Intracellular Enzyme Sequestration.

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 cells and may provide insights for understanding intracellular liquid condensates and a new strategy for modulating protein-protein interactions.

SUBMITTER: Feng Z

PROVIDER: S-EPMC6470013 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Instructed Assembly of Peptides for Intracellular Enzyme Sequestration.

Feng Zhaoqianqi Z Wang Huaimin H Xu Bing B

Journal of the American Chemical Society 20181121 48

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 o ...[more]

PMID: 30452246

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Project description:Recent studies have demonstrated that enzyme-instructed self-assembly (EISA) in extra- or intracellular environments can serve as a multistep process for controlling cell fate. There is little knowledge, however, about the kinetics of EISA in the complex environments in or around cells. Here, we design and synthesize three dipeptidic precursors (ld-1-SO3, dl-1-SO3, dd-1-SO3), consisting of diphenylalanine (l-Phe-d-Phe, d-Phe-l-Phe, d-Phe-d-Phe, respectively) as the backbone, which are capped by 2-(naphthalen-2-yl)acetic acid at the N-terminal and by 2-(4-(2-aminoethoxy)-4-oxobutanamido)ethane-1-sulfonic acid at the C-terminal. On hydrolysis by carboxylesterases (CES), these precursors result in hydrogelators, which self-assemble in water at different rates. Whereas all three precursors selectively kill cancer cells, especially high-grade serous ovarian carcinoma cells, by undergoing intracellular EISA, dl-1-SO3 and dd-1-SO3 exhibit the lowest and the highest activities, respectively, against the cancer cells. This trend inversely correlates with the rates of converting the precursors to the hydrogelators in phosphate-buffered saline. Because CES exists both extra- and intracellularly, we use kinetic modeling to analyze the kinetics of EISA inside cells and to calculate the cytotoxicity of each precursor for killing cancer cells. Our results indicate that (i) the stereochemistry of the precursors affects the morphology of the nanostructures formed by the hydrogelators, as well as the rate of enzymatic conversion; (ii) decreased extracellular hydrolysis of precursors favors intracellular EISA inside the cells; (iii) the inherent features ( e.g., self-assembling ability and morphology) of the EISA molecules largely dictate the cytotoxicity of intracellular EISA. As the kinetic analysis of intracellular EISA, this work elucidates how the stereochemistry modulates EISA in the complex extra- and/or intracellular environment for developing anticancer molecular processes. Moreover, it provides insights for understanding the kinetics and cytotoxicity of aggregates of aberrant proteins or peptides formed inside and outside cells.

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Instructed Assembly of Peptides for Intracellular Enzyme Sequestration.

Publications

Instructed Assembly of Peptides for Intracellular Enzyme Sequestration.

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