The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity
The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity
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DOI：
10.1093/hmg/ddi439
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发表时间：
2006-01-15
影响因子：
3.5
通讯作者：
Ueffing, M
中科院分区：
文献类型：
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作者：
Gloeckner, CJ;Kinkl, N;Ueffing, M
富含亮氨酸重复序列激酶2基因（LRRK 2）的突变最近已被确定在常染色体显性遗传迟发性帕金森病（PD）的家庭。LRRK 2蛋白由多个结构域组成，属于Roco家族，一个新的Ras/GTfamily超家族。除了GTdR（Roc）结构域之外，它还包含预测的激酶结构域，与MAP激酶具有同源性。使用细胞分级分离和免疫荧光显微镜，我们表明，LRRK 2定位于细胞质中，并与细胞膜结构。纯化的LRRK 2蛋白显示自身激酶活性。疾病相关的I2020 T突变体显示出与野生型蛋白质相比，在体外自磷酸化显著增加，接近40%。这表明I2020 T突变引起的PD病理学与LRRK 2激酶活性的增加而不是丧失相关。
Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been recently identified in families with autosomal dominant late-onset Parkinson disease (PD). The LRRK2 protein consists of multiple domains and belongs to the Roco family, a novel group of the Ras/GTPase superfamily. Besides the GTPase (Roc) domain, it contains a predicted kinase domain, with homology to MAP kinase kinase kinases. Using cell fractionation and immunofluorescence microscopy, we show that LRRK2 is localized in the cytoplasm and is associated with cellular membrane structures. The purified LRRK2 protein demonstrates autokinase activity. The disease-associated I2020T mutant shows a significant increase in autophosphorylation of similar to 40% in comparison to wild-type protein in vitro. This suggests that the pathology of PD caused by the I2020T mutation is associated with an increase rather than a loss in LRRK2 kinase activity.