The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity
The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity
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DOI：
10.1093/hmg/ddg344
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发表时间：
2003-12-01
影响因子：
3.5
通讯作者：
Pittman, RN
中科院分区：
文献类型：
--
作者：
Burnett, B;Li, FS;Pittman, RN
泛素-蛋白酶体途径在以蛋白质错误折叠和聚集为特征的神经退行性疾病的病理学中起着关键作用。本研究中的数据表明，多聚谷氨酰胺神经退行性疾病蛋白，共济失调蛋白-3（AT 3），在泛素-蛋白酶体途径中发挥作用。AT 3含有一个泛素相互作用基序（UIM）结构域，该结构域结合多聚泛素化蛋白，强烈偏好含有四个或更多个泛素的链。突变第一个UIM（L229 A）中的保守亮氨酸几乎完全消除了与多聚泛素链的结合，而第二个UIM（L249 A）中的类似突变也抑制了与多聚泛素链的结合，但程度较低。野生型和病理性AT 3都增加了由泛素-蛋白酶体途径降解的短寿命GFP的细胞水平。AT 3具有泛素蛋白酶的几种特性，包括通过从多聚泛素链中去除泛素来减少I-125-溶菌酶的多聚泛素化，切割泛素蛋白酶底物，以及结合特异性泛素蛋白酶抑制剂泛素-醛。突变AT 3中预测的催化半胱氨酸抑制这些泛素蛋白酶活性中的每一种。结合和切割泛素化蛋白的能力与AT 3在泛素-蛋白酶体系统中发挥作用一致。这提出了倾向于错误折叠和聚集的病理性AT 3可能暴露于聚集倾向性错误折叠/变性蛋白作为其正常功能的一部分的可能性。
The ubiquitin-proteasome pathway is critically involved in the pathology of neurodegenerative diseases characterized by protein misfolding and aggregation. Data in the present study suggest that the polyglutamine neurodegenerative disease protein, ataxin-3 (AT3), functions in the ubiquitin-proteasome pathway. AT3 contains an ubiquitin interaction motif (UIM) domain that binds polyubiquitylated proteins with a strong preference for chains containing four or more ubiquitins. Mutating the conserved leucine in the first UIM (L229A) almost totally eliminates binding to polyubiquitin chains while a similar mutation in the second UIM (L249A) also inhibits binding to polyubiquitin chains but to a lesser extent. Both wild-type and pathological AT3 increase cellular levels of a short-lived GFP that is degraded by the ubiquitin-proteasome pathway. AT3 has several properties characteristic of ubiquitin proteases including decreasing polyubiquitylation of I-125-lysozyme by removing ubiquitin from polyubiquitin chains, cleaving a ubiquitin protease substrate, and binding the specific ubiquitin protease inhibitor, ubiquitin-aldehyde. Mutating the predicted catalytic cysteine in AT3 inhibits each of these ubiquitin protease activities. The ability to bind and cleave ubiquitylated proteins is consistent with AT3 playing a role in the ubiquitin-proteasome system. This raises the possibility that pathological AT3, which tends to misfold and aggregate, may be exposed to aggregate-prone misfolded/denatured proteins as part of its normal function.