Allosteric Inhibition of Parkinson's-Linked LRRK2 by Constrained Peptides.

Autor:	Helton LG; Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602, United States., Soliman A; Department of Cell Biochemistry, University of Groningen, 9747 Groningen, The Netherlands., von Zweydorf F; DZNE, German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany., Kentros M; Center for Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece., Manschwetus JT; Department of Biochemistry, Institute for Biology, University of Kassel, 34132, Kassel, Germany., Hall S; Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602, United States., Gilsbach B; DZNE, German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany., Ho FY; Department of Cell Biochemistry, University of Groningen, 9747 Groningen, The Netherlands., Athanasopoulos PS; Department of Cell Biochemistry, University of Groningen, 9747 Groningen, The Netherlands., Singh RK; VIB-VUB Center for Structural Biology, Pleinlaan 2, 1050 Brussels, Belgium.; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium., LeClair TJ; Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602, United States., Versées W; VIB-VUB Center for Structural Biology, Pleinlaan 2, 1050 Brussels, Belgium.; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium., Raimondi F; Laboratorio di Biologia Bio@SNS, Scuola Normale Superiore, 56126, Pisa, Italy., Herberg FW; Department of Biochemistry, Institute for Biology, University of Kassel, 34132, Kassel, Germany., Gloeckner CJ; DZNE, German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany.; Core Facility for Medical Bioanalytics, Center for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, 72076 Tübingen, Germany., Rideout H; Center for Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece., Kortholt A; Department of Cell Biochemistry, University of Groningen, 9747 Groningen, The Netherlands.; Department of Pharmacology, Innovative Technologies Application and Research Center, Suleyman Demirel University, 32260 Isparta, Turkey., Kennedy EJ; Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602, United States.
Jazyk:	angličtina
Zdroj:	ACS chemical biology [ACS Chem Biol] 2021 Nov 19; Vol. 16 (11), pp. 2326-2338. Date of Electronic Publication: 2021 Sep 08.
DOI:	10.1021/acschembio.1c00487
Abstrakt:	Leucine-Rich Repeat Kinase 2 (LRRK2) is a large, multidomain protein with dual kinase and GTPase function that is commonly mutated in both familial and idiopathic Parkinson's Disease (PD). While dimerization of LRRK2 is commonly detected in PD models, it remains unclear whether inhibition of dimerization can regulate catalytic activity and pathogenesis. Here, we show constrained peptides that are cell-penetrant, bind LRRK2, and inhibit LRRK2 activation by downregulating dimerization. We further show that inhibited dimerization decreases kinase activity and inhibits ROS production and PD-linked apoptosis in primary cortical neurons. While many ATP-competitive LRRK2 inhibitors induce toxicity and mislocalization of the protein in cells, these constrained peptides were found to not affect LRRK2 localization. The ability of these peptides to inhibit pathogenic LRRK2 kinase activity suggests that disruption of dimerization may serve as a new allosteric strategy to downregulate PD-related signaling pathways.
Databáze:	MEDLINE
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