R1441C突变改变了LRRK2的ROC结构域的折叠特性。
The R1441C mutation alters the folding properties of the ROC domain of LRRK2.
作者信息
Li Yongchao, Dunn Laura, Greggio Elisa, Krumm Brian, Jackson Graham S, Cookson Mark R, Lewis Patrick A, Deng Junpeng
机构信息
Department of Biochemistry and Molecular biology, Oklahoma State University, Stillwater, OK 74078, USA.
出版信息
Biochim Biophys Acta. 2009 Dec;1792(12):1194-7. doi: 10.1016/j.bbadis.2009.09.010. Epub 2009 Sep 23.
Abstract
LRRK2 is a 250 kDa multidomain protein, mutations in which cause familial Parkinson's disease. Previously, we have demonstrated that the R1441C mutation in the ROC domain decreases GTPase activity. Here we show that the R1441C alters the folding properties of the ROC domain, lowering its thermodynamic stability. Similar to small GTPases, binding of different guanosine nucleotides alters the stability of the ROC domain, suggesting that there is an alteration in conformation dependent on GDP or GTP occupying the active site. GTP/GDP bound state also alters the self-interaction of the ROC domain, accentuating the impact of the R1441C mutation on this property. These data suggest a mechanism whereby the R1441C mutation can reduce the GTPase activity of LRRK2, and highlights the possibility of targeting the stability of the ROC domain as a therapeutic avenue in LRRK2 disease.
摘要
LRRK2是一种250 kDa的多结构域蛋白，其突变会导致家族性帕金森病。此前，我们已经证明ROC结构域中的R1441C突变会降低GTP酶活性。在此我们表明，R1441C改变了ROC结构域的折叠特性，降低了其热力学稳定性。与小GTP酶类似，不同鸟苷核苷酸的结合会改变ROC结构域的稳定性，这表明存在一种依赖于占据活性位点的GDP或GTP的构象改变。GTP/GDP结合状态也会改变ROC结构域的自身相互作用，突出了R1441C突变对该特性的影响。这些数据提示了一种机制，通过该机制R1441C突变可降低LRRK2的GTP酶活性，并突出了将ROC结构域的稳定性作为LRRK2疾病治疗途径的可能性。
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