The Parkinson disease gene LRRK2:: Evolutionary and structural insights
The Parkinson disease gene LRRK2:: Evolutionary and structural insights
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DOI：
10.1093/molbev/msl114
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发表时间：
2006-12-01
影响因子：
10.7
通讯作者：
Marin, Ignacio
中科院分区：
文献类型：
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作者：
Marin, Ignacio
人类富含亮氨酸重复序列激酶2（LRRK 2）基因突变与家族性和散发性帕金森病（PD）相关。LRRK 2属于一个被称为Roco的基因家族。Roco基因编码具有几个蛋白质结构域的大蛋白质。特别是，所有Roco蛋白都有一个特征性的GTdR结构域，名为Roc，加上一个未知功能的结构域，名为COR。此外，LRRK 2和其他几种Roco蛋白也含有蛋白激酶结构域。在这项研究中，我使用的COR，ROC和激酶结构域的Roco蛋白质的系统发育和结构分析的组合来描述LRRK 2的起源和进化历史。使用这些结构域的系统发育分析表明，LRRK 2出现从原口-后口分裂后发生的重复。复制之后，LRRK 2蛋白获得了一种特定类型的N-末端重复序列，这是第一次描述。这种重复在LRRK 2的旁系同源物编码的蛋白质（称为LRRK 1）或原口体LRRK蛋白中不存在。这些结果表明果蝇或隐杆线虫LRRK基因可能不是了解人类LRRK 2功能的良好模型。黏菌盘基网柄菌中的基因与动物LRRK基因中发现的结构非常相似，包括蛋白激酶结构域。然而，系统发育分析表明，这种结构相似性是由于独立收购的远亲蛋白激酶域。最后，我确认在一个广泛的序列分析，Roc GTPases域相关，但仍然有很大的不同，从小GTP酶，如Rab，Ras，或Rho。基于已知激酶结构的建模表明，导致常见PD的LRRK 2突变可能会改变LRRK 2蛋白的局部三维折叠，而不会影响其整体结构。
Mutations in the human leucine-rich repeat kinase 2 (LRRK2) gene are associated with both familial and sporadic Parkinson disease (PD). LRRK2 belongs to a gene family known as Roco. Roco genes encode for large proteins with several protein domains. Particularly, all Roco proteins have a characteristic GTPase domain, named Roc, plus a domain of unknown function called COR. In addition, LRRK2 and several other Roco proteins also contain a protein kinase domain. In this study, I use a combination of phylogenetic and structural analyses of the COR, Roc, and kinase domains present in Roco proteins to describe the origin and evolutionary history of LRRK2. Phylogenetic analyses using these domains demonstrate that LRRK2 emerged from a duplication that occurred after the protostome-deuterostome split. The duplication was followed by the acquisition by LRRK2 proteins of a specific type of N-terminal repeat, described here for the first time. This repeat is absent in the proteins encoded by the paralogs of LRRK2, called LRRK1 or in protostome LRRK proteins. These results suggest that Drosophila or Caenorhabditis LRRK genes may not be good models to understand human LRRK2 function. Genes in the slime mold Dictyostelium discoideum with structures very similar to those found in animal LRRK genes, including the protein kinase domain, have been described. However, phylogenetic analyses suggest that this structural similarity is due to independent acquisitions of distantly related protein kinase domains. Finally, I confirm in an extensive sequence analysis that the Roc GTPase domain is related but still substantially different from small GTPases, such as Rab, Ras, or Rho. Modeling based on known kinase structures suggests that mutations in LRRK2 that cause familiar PD may alter the local 3-dimensional folding of the LRRK2 protein without affecting its overall structure.