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Allosteric Inhibition of Parkinson’s-Linked LRRK2 by Constrained Peptides
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2021-09-08 , DOI: 10.1021/acschembio.1c00487 Leah G Helton 1 , Ahmed Soliman 2 , Felix von Zweydorf 3 , Michalis Kentros 4 , Jascha T Manschwetus 5 , Scotty Hall 1 , Bernd Gilsbach 3 , Franz Y Ho 2 , Panagiotis S Athanasopoulos 2 , Ranjan K Singh 6, 7 , Timothy J LeClair 1 , Wim Versées 6, 7 , Francesco Raimondi 8 , Friedrich W Herberg 5 , Christian Johannes Gloeckner 3, 9 , Hardy Rideout 4 , Arjan Kortholt 2, 10 , Eileen J Kennedy 1
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2021-09-08 , DOI: 10.1021/acschembio.1c00487 Leah G Helton 1 , Ahmed Soliman 2 , Felix von Zweydorf 3 , Michalis Kentros 4 , Jascha T Manschwetus 5 , Scotty Hall 1 , Bernd Gilsbach 3 , Franz Y Ho 2 , Panagiotis S Athanasopoulos 2 , Ranjan K Singh 6, 7 , Timothy J LeClair 1 , Wim Versées 6, 7 , Francesco Raimondi 8 , Friedrich W Herberg 5 , Christian Johannes Gloeckner 3, 9 , Hardy Rideout 4 , Arjan Kortholt 2, 10 , Eileen J Kennedy 1
Affiliation
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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.
中文翻译：
受限肽对帕金森氏症相关 LRRK2 的变构抑制
富含亮氨酸的重复激酶 2 (LRRK2) 是一种大型多结构域蛋白，具有双重激酶和 GTPase 功能，通常在家族性和特发性帕金森病 (PD) 中发生突变。虽然在 PD 模型中通常检测到 LRRK2 的二聚化，但仍不清楚抑制二聚化是否可以调节催化活性和发病机制。在这里，我们展示了具有细胞渗透性、结合 LRRK2 并通过下调二聚化抑制 LRRK2 活化的受限肽。我们进一步表明，抑制二聚化会降低原代皮层神经元的激酶活性并抑制 ROS 产生和 PD 相关的细胞凋亡。虽然许多 ATP 竞争性 LRRK2 抑制剂会诱导细胞中蛋白质的毒性和错误定位，但发现这些受限肽不会影响 LRRK2 定位。
更新日期：2021-09-08
中文翻译：
受限肽对帕金森氏症相关 LRRK2 的变构抑制
富含亮氨酸的重复激酶 2 (LRRK2) 是一种大型多结构域蛋白，具有双重激酶和 GTPase 功能，通常在家族性和特发性帕金森病 (PD) 中发生突变。虽然在 PD 模型中通常检测到 LRRK2 的二聚化，但仍不清楚抑制二聚化是否可以调节催化活性和发病机制。在这里，我们展示了具有细胞渗透性、结合 LRRK2 并通过下调二聚化抑制 LRRK2 活化的受限肽。我们进一步表明，抑制二聚化会降低原代皮层神经元的激酶活性并抑制 ROS 产生和 PD 相关的细胞凋亡。虽然许多 ATP 竞争性 LRRK2 抑制剂会诱导细胞中蛋白质的毒性和错误定位，但发现这些受限肽不会影响 LRRK2 定位。
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