Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin-like domain
Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin-like domain
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DOI：
10.1038/sj.embor.embor764
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发表时间：
2003-03-01
期刊：
影响因子：
7.7
通讯作者：
Kato, K
中科院分区：
文献类型：
--
作者：
Sakata, E;Yamaguchi, Y;Kato, K
Parkin是常染色体隐性青少年帕金森病（AR-JP）致病基因的产物，是一种环型E3泛素连接酶，具有氨基末端泛素样（Ubl）结构域。虽然在AR-JP患者中发现了导致Ubl结构域42位Arg向Pro取代的单一突变（Arg 42突变），但该结构域的功能尚不清楚。在这项研究中，我们通过核磁共振确定了parkin的Ubl域的三维结构，特别是通过大量使用骨架N-15-H-1残余偶极耦合数据。化学位移-扰动数据的检验表明，parkin Ubl结构域通过包含位置42的parkin区域结合26S蛋白酶体的Rpn10亚基。我们的研究结果表明，Arg 42突变诱导了Ubl的rpn10结合位点的构象变化，导致parkin的蛋白酶体结合受损，这可能是AR-JP的原因。
Parkin, a product of the causative gene of autosomal-recessive juvenile parkinsonism (AR-JP), is a RING-type E3 ubiquitin ligase and has an amino-terminal ubiquitin-like (Ubl) domain. Although a single mutation that causes an Arg to Pro substitution at position 42 of the Ubl domain (the Arg 42 mutation) has been identified in AR-JP patients, the function of this domain is not clear. In this study, we determined the three-dimensional structure of the Ubl domain of parkin by NMR, in particular by extensive use of backbone N-15-H-1 residual dipolar-coupling data. Inspection of chemical-shift-perturbation data showed that the parkin Ubl domain binds the Rpn10 subunit of 26S proteasomes via the region of parkin that includes position 42. Our findings suggest that the Arg 42 mutation induces a conformational change in the Rpn10-binding site of Ubl, resulting in impaired proteasomal binding of parkin, which could be the cause of AR-JP.