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Development of an Acrylamide-Based Inhibitor of Protein S-Acylation

preprint
submitted on 08.02.2021, 18:16 and posted on 09.02.2021, 12:59 by Saara-Anne Azizi, Tong Lan, Clémence Delalande, Rahul Kathayat, Bryan Dickinson

Protein S-acylation is a dynamic lipid post-translational modification that can modulate the localization and activity of target proteins. In humans, the installation of the lipid onto target proteins is catalyzed by a family of 23 Asp-His-His-Cys domain-containing protein acyltransferases (DHHC-PATs). DHHCs are increasingly recognized as critical players in cellular signaling events and in human disease. However, progress elucidating the functions and mechanisms of DHHC “writers” has been hampered by a lack of chemical tools to perturb their activity in live cells. Herein, we report the synthesis and characterization of PATi, a pan- DHHC inhibitor more potent than 2-bromopalmitate (2BP), the most commonly used DHHC inhibitor in the field. Possessing an acrylamide warhead, PATi pairs its gain in potency with decreases in both toxicity and inhibition of the S-acylation eraser enzymes – two of the major weaknesses of 2BP. Our studies show that PATi engages with DHHC family proteins in cells, inhibits protein S-acylation, and disrupts DHHC-regulated cellular events. PATi represents an improved chemical tool for untangling the complexities of DHHC-mediated cell signaling by protein S-acylation.

Funding

Molecular imaging approaches to interrogate mammalian signaling by lysine acylation

National Institute of General Medical Sciences

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Identifying the mechanisms and biological impact of ERK lipidation in metabolic signaling

National Institute of Diabetes and Digestive and Kidney Diseases

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Chemical approaches to interrogate the role of DHHCs in dynamic proteome lipid signaling

Swiss National Science Foundation

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History

Email Address of Submitting Author

dickinson@uchicago.edu

Institution

University of Chicago

Country

United States

ORCID For Submitting Author

0000-0002-9616-1911

Declaration of Conflict of Interest

R.S.K. and B.C.D. have a patent on the DPP technology used in this work.

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