Department of Pharmacology, University of California, San Diego, California, United States of America.
Department of Biochemistry, University of Kassel, Kassel, Germany.
PLoS Biol. 2022 Feb 22;20(2):e3001427. doi: 10.1371/journal.pbio.3001427. eCollection 2022 Feb.
The 2 major molecular switches in biology, kinases and GTPases, are both contained in the Parkinson disease-related leucine-rich repeat kinase 2 (LRRK2). Using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics (MD) simulations, we generated a comprehensive dynamic allosteric portrait of the C-terminal domains of LRRK2 (LRRK2RCKW). We identified 2 helices that shield the kinase domain and regulate LRRK2 conformation and function. One helix in COR-B (COR-B Helix) tethers the COR-B domain to the αC helix of the kinase domain and faces its activation loop, while the C-terminal helix (Ct-Helix) extends from the WD40 domain and interacts with both kinase lobes. The Ct-Helix and the N-terminus of the COR-B Helix create a "cap" that regulates the N-lobe of the kinase domain. Our analyses reveal allosteric sites for pharmacological intervention and confirm the kinase domain as the central hub for conformational control.
生物学中的 2 个主要分子开关，激酶和 GTP 酶，都包含在帕金森病相关的富亮氨酸重复激酶 2（LRRK2）中。我们使用氢氘交换质谱（HDX-MS）和分子动力学（MD）模拟，生成了 LRRK2 （LRRK2RCKW）C 端结构域的全面动态变构图。我们确定了 2 个可以屏蔽激酶结构域并调节 LRRK2 构象和功能的螺旋。COR-B 结构域中的一个螺旋（COR-B 螺旋）将 COR-B 结构域与激酶结构域的 αC 螺旋连接，并面向其激活环，而 C 端螺旋（Ct-螺旋）从 WD40 结构域延伸，并与两个激酶结构域相互作用。Ct-螺旋和 COR-B 螺旋的 N 端形成一个“盖子”，调节激酶结构域的 N 结构域。我们的分析揭示了药理学干预的变构位点，并证实了激酶结构域是构象控制的中心枢纽。
