L166P mutant DJ-1, causative for recessive Parkinson's disease, is degraded through the ubiquitin-proteasome system
L166P mutant DJ-1, causative for recessive Parkinson's disease, is degraded through the ubiquitin-proteasome system
复制标题
DOI：
10.1074/jbc.m304272200
复制
发表时间：
2003-09-19
影响因子：
4.8
通讯作者：
Cookson, MR
中科院分区：
文献类型：
--
作者：
Miller, DW;Ahmad, R;Cookson, MR
最近有报道称，1号染色体上的基因DJ-1突变与隐性早发性帕金森病有关。虽然一个突变是一个大的缺失，预计会产生有效的基因敲除，第二个是一个点突变，L166 P，其对蛋白质功能的确切影响尚不清楚。在本研究中，我们表明，L166 P不稳定DJ-1蛋白，并通过泛素-蛋白酶体系统促进其降解。双突变体（K130 R，L166 P）比L166 P更稳定，表明该赖氨酸残基有助于蛋白质的稳定性。野生型和L166 P形式的蛋白质的亚细胞定位大致相似，表明突变的影响主要是对蛋白质的稳定性。这些观察结果让人联想到其他隐性基因突变，这些突变会导致有效的功能丧失。L166 P突变具有促进DJ-1降解的简单作用，从而减少细胞内的净DJ-1蛋白。
Mutations in a gene on chromosome 1, DJ-1, have been reported recently to be associated with recessive, early-onset Parkinson's disease. While one mutation is a large deletion that is predicted to produce an effective knockout of the gene, the second is a point mutation, L166P, whose precise effects on protein function are unclear. In the present study, we show that L166P destabilizes DJ-1 protein and promotes its degradation through the ubiquitin-proteasome system. A double mutant (K130R, L166P) was more stable than L166P, suggesting that this lysine residue contributes to stability of the protein. Subcellular localization was broadly similar for both wild type and L166P forms of the protein, indicating that the effect of the mutation is predominantly on protein stability. These observations are reminiscent of other recessive gene mutations that produce an effective loss of function. The L166P mutation has the simple effect of promoting DJ-1 degradation, thereby reducing net DJ-1 protein within the cell.