A cluster of palmitoylated cysteines are essential for aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis.
A cluster of palmitoylated cysteines are essential for aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis.
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DOI：
10.1038/s41598-017-00036-8
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发表时间：
2017-01-31
影响因子：
4.6
通讯作者：
Chamberlain LH
中科院分区：
文献类型：
--
作者：
Diez-Ardanuy C;Greaves J;Munro KR;Tomkinson NC;Chamberlain LH
常染色体显性成人型神经元蜡样质脂褐质沉积症（ANCL）是由编码半胱氨酸串蛋白α（CSPα）的DNAJC 5基因突变引起的。导致半胱氨酸串结构域中亮氨酸-115被精氨酸取代（L115 R）或相邻亮氨酸-116缺失（L116）的致病突变导致CSPα形成高分子量SDS抗性聚集体，这些聚集体也存在于患者的死后脑组织中。这些突变体聚集体的形成和稳定性与半胱氨酸串结构域的棕榈酰化有关，然而驱动聚集的突变体蛋白质的区域尚未确定。研究了半胱氨酸串结构域中特定残基的重要性，揭示了棕榈酰化半胱氨酸的中心核心对于ANCL CSPα突变体的聚集是必需的。有趣的是，与野生型CSPα相比，ANCL CSPα突变体的棕榈酰化单体的寿命较短，这表明突变体的脱棕榈酰化速率更快，或者它们以时间依赖性方式消耗成高分子量聚集体。这些发现为CSPα的特征提供了新的见解，这些特征在L115 R/CCL 116突变的情况下促进聚集，并揭示了突变蛋白的棕榈酰化单体寿命的变化。
Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is caused by mutation of the DNAJC5 gene encoding cysteine string protein alpha (CSPα). The disease-causing mutations, which result in substitution of leucine-115 with an arginine (L115R) or deletion of the neighbouring leucine-116 (∆L116) in the cysteine-string domain cause CSPα to form high molecular weight SDS-resistant aggregates, which are also present in post-mortem brain tissue from patients. Formation and stability of these mutant aggregates is linked to palmitoylation of the cysteine-string domain, however the regions of the mutant proteins that drive aggregation have not been determined. The importance of specific residues in the cysteine-string domain was investigated, revealing that a central core of palmitoylated cysteines is essential for aggregation of ANCL CSPα mutants. Interestingly, palmitoylated monomers of ANCL CSPα mutants were shown to be short-lived compared with wild-type CSPα, suggesting that the mutants either have a faster rate of depalmitoylation or that they are consumed in a time-dependent manner into high molecular weight aggregates. These findings provide new insight into the features of CSPα that promote aggregation in the presence of L115R/∆L116 mutations and reveal a change in the lifetime of palmitoylated monomers of the mutant proteins.