GTP binding regulates cellular localization of Parkinson's disease-associated LRRK2.
GTP binding regulates cellular localization of Parkinson's disease-associated LRRK2.
复制标题
DOI：
10.1093/hmg/ddx161
复制
发表时间：
2017-07-15
影响因子：
3.5
通讯作者：
Hilfiker S
中科院分区：
文献类型：
--
作者：
Blanca Ramírez M;Lara Ordóñez AJ;Fdez E;Madero-Pérez J;Gonnelli A;Drouyer M;Chartier-Harlin MC;Taymans JM;Bubacco L;Greggio E;Hilfiker S
富亮氨酸重复激酶2 （LRRK2）的突变是家族性帕金森病（PD）的最常见原因，序列变异改变了散发性PD的风险。先前的研究表明，LRRK2与微管（MTs）相互作用并改变微管介导的囊泡运输过程。然而，这种相互作用所需的LRRK2分子决定因素仍然未知。在这里，我们报告了大多数致病性LRRK2突变体导致LRRK2重新定位到丝状结构，这些丝状结构与mt亚群共定位，并且在药理学上LRRK2激酶抑制时可以看到相同的重新定位。与MTs的明显共定位与LRRK2激酶活性的改变无关，而是与GTP结合的增加有关。破坏GTP结合的合成突变以及LRRK2 GTP结合抑制剂会严重干扰致病性突变体和激酶抑制的LRRK2的异常定位。相反，在渗透细胞中添加一种不可水解的GTP类似物会增强致病性或激酶抑制的LRRK2与MT的关联。我们的数据阐明了致病性LRRK2突变体或药理学上激酶抑制的LRRK2与MT关联增加的机制，并对下游MT介导的转运事件有影响。
Mutations in leucine-rich repeat kinase 2 (LRRK2) comprise the most common cause of familial Parkinson's disease (PD), and sequence variants modify risk for sporadic PD. Previous studies indicate that LRRK2 interacts with microtubules (MTs) and alters MT-mediated vesicular transport processes. However, the molecular determinants within LRRK2 required for such interactions have remained unknown. Here, we report that most pathogenic LRRK2 mutants cause relocalization of LRRK2 to filamentous structures which colocalize with a subset of MTs, and an identical relocalization is seen upon pharmacological LRRK2 kinase inhibition. The pronounced colocalization with MTs does not correlate with alterations in LRRK2 kinase activity, but rather with increased GTP binding. Synthetic mutations which impair GTP binding, as well as LRRK2 GTP-binding inhibitors profoundly interfere with the abnormal localization of both pathogenic mutant as well as kinase-inhibited LRRK2. Conversely, addition of a non-hydrolyzable GTP analog to permeabilized cells enhances the association of pathogenic or kinase-inhibited LRRK2 with MTs. Our data elucidate the mechanism underlying the increased MT association of select pathogenic LRRK2 mutants or of pharmacologically kinase-inhibited LRRK2, with implications for downstream MT-mediated transport events.
登录
查看更多内容
影响因子：
4.4
作者：
Gloeckner, Christian Johannes;Boldt, Karsten;Ueffing, Marius
通讯作者：
Ueffing, Marius
影响因子：
4.7
作者：
Gillardon, Frank
通讯作者：
Gillardon, Frank
影响因子：
3.5
作者：
Biosa, Alice;Trancikova, Alzbeta;Moore, Darren J.
通讯作者：
Moore, Darren J.
c-Jun N 末端激酶 (JNK) 与 Gsk3beta 配合调节 Dishevelled 介导的微管稳定性。
影响因子：
--
作者：
Ciani, Lorenza;Salinas, Patricia C.
通讯作者：
Salinas, Patricia C.
影响因子：
11.2
作者：
Funayama, M;Hasegawa, K;Obata, F
通讯作者：
Obata, F