The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation
The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation
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DOI：
10.1074/jbc.m708718200
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发表时间：
2008-06-13
影响因子：
4.8
通讯作者：
Cookson, Mark R.
中科院分区：
文献类型：
--
作者：
Greggio, Elisa;Zambrano, Ibardo;Cookson, Mark R.
富含亮氨酸重复序列激酶2（LRRK 2）的突变是家族性和明显散发性帕金森病的常见原因。LRRK 2是一种具有自磷酸化活性的多结构域蛋白激酶。先前已经表明，LRRK 2的激酶活性是神经元毒性所必需的，这表明理解激酶激活和调节的机制对于开发用于帕金森病治疗的特异性激酶抑制剂可能是重要的。在这里，我们表明，LRRK 2主要存在于天然条件下的二聚体，一种状态，似乎是稳定的多个域-域的相互作用。此外，自磷酸化活性需要完整的C末端，而不是N末端。我们确定了两个残基的激活回路，有助于调节LRRK 2的自磷酸化。最后，我们证明LRRK 2进行分子内自磷酸化。总之，这些结果提供了深入了解LRRK 2激酶活性的机制和调节。
Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial and apparently sporadic Parkinson disease. LRRK2 is a multidomain protein kinase with autophosphorylation activity. It has previously been shown that the kinase activity of LRRK2 is required for neuronal toxicity, suggesting that understanding the mechanism of kinase activation and regulation may be important for the development of specific kinase inhibitors for Parkinson disease treatment. Here, we show that LRRK2 predominantly exists as a dimer under native conditions, a state that appears to be stabilized by multiple domain-domain interactions. Furthermore, an intact C terminus, but not N terminus, is required for autophosphorylation activity. We identify two residues in the activation loop that contribute to the regulation of LRRK2 autophosphorylation. Finally, we demonstrate that LRRK2 undergoes intramolecular autophosphorylation. Together, these results provide insight into the mechanism and regulation of LRRK2 kinase activity.