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The In Situ Structure of Parkinson's Disease-Linked LRRK2.
Cell ( IF 45.5 ) Pub Date : 2020-08-11 , DOI: 10.1016/j.cell.2020.08.004
Reika Watanabe 1 , Robert Buschauer 1 , Jan Böhning 1 , Martina Audagnotto 1 , Keren Lasker 2 , Tsan-Wen Lu 3 , Daniela Boassa 4 , Susan Taylor 5 , Elizabeth Villa 1
Affiliation  

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson’s disease. LRRK2 is a multi-domain protein containing a kinase and GTPase. Using correlative light and electron microscopy, in situ cryo-electron tomography, and subtomogram analysis, we reveal a 14-Å structure of LRRK2 bearing a pathogenic mutation that oligomerizes as a right-handed double helix around microtubules, which are left-handed. Using integrative modeling, we determine the architecture of LRRK2, showing that the GTPase and kinase are in close proximity, with the GTPase closer to the microtubule surface, whereas the kinase is exposed to the cytoplasm. We identify two oligomerization interfaces mediated by non-catalytic domains. Mutation of one of these abolishes LRRK2 microtubule-association. Our work demonstrates the power of cryo-electron tomography to generate models of previously unsolved structures in their cellular environment.



中文翻译:

帕金森病相关 LRRK2 的原位结构。

富含亮氨酸重复激酶 2 (LRRK2) 的突变是家族性帕金森病的最常见原因。LRRK2 是一种包含激酶和 GTP 酶的多域蛋白。使用相关光和电子显微镜,原位通过冷冻电子断层扫描和亚断层扫描分析,我们揭示了 LRRK2 的 14 Å 结构,该结构带有致病突变,该突变寡聚化为围绕左旋微管的右旋双螺旋。使用综合建模,我们确定了 LRRK2 的结构,表明 GTPase 和激酶非常接近,GTPase 更靠近微管表面,而激酶暴露于细胞质。我们确定了由非催化域介导的两个寡聚化界面。其中之一的突变消除了 LRRK2 微管关联。我们的工作证明了冷冻电子断层扫描在细胞环境中生成以前未解决的结构模型的能力。

更新日期:2020-09-18
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