The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis
The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis
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DOI：
10.1073/pnas.080508097
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发表时间：
2000-04-25
影响因子：
11.1
通讯作者：
Clardy, J
中科院分区：
文献类型：
--
作者：
Bellizzi, JJ;Widom, J;Clardy, J
棕榈酰蛋白硫酯酶1（PPT 1）是一种从修饰蛋白质的半胱氨酸残基中去除脂肪酰基的溶酶体酶，其突变会导致致命的遗传性神经退行性疾病婴儿神经元蜡样脂褐质沉积症。未消化底物的积累导致与临床症状相关的神经元储存体的形成。最近发现了不太严重的PPT 1缺乏症，它们是由一组独特的PPT 1突变引起的，其中一些突变保留了少量的硫酯酶活性。我们已经确定了PPT 1的晶体结构，并没有绑定棕榈酸酯通过使用多波长异常衍射相位。该结构揭示了具有由Ser 115-His 289-Asp 233组成的催化三联体的α/β-水解酶折叠，并提供了与PPT 1突变相关的表型的结构基础的见解。
Mutations in palmitoyl-protein thioesterase 1 (PPT1), a lysosomal enzyme that removes fatty acyl groups from cysteine residues in modified proteins, cause the fatal inherited neurodegenerative disorder infantile neuronal ceroid lipofuscinosis. The accumulation of undigested substrates leads to the formation of neuronal storage bodies that are associated with the clinical symptoms. Less severe forms of PPT1 deficiency have been found recently that are caused by a distinct set of PPT1 mutations, some of which retain a small amount of thioesterase activity. We have determined the crystal structure of PPT1 with and without bound palmitate by using multiwavelength anomalous diffraction phasing. The structure reveals an alpha/beta-hydrolase fold with a catalytic triad composed of Ser115-His289-Asp233 and provides insights into the structural basis for the phenotypes associated with PPT1 mutations.