The mechanism of sphingolipid processing revealed by a GALC-SapA complex structure
The mechanism of sphingolipid processing revealed by a GALC-SapA complex structure
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DOI：
10.1101/112029
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发表时间：
2017-02
期刊：
影响因子：
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通讯作者：
C. Hill;Georgia M. Cook;S. J. Spratley;S. C. Graham;J. Deane
中科院分区：
文献类型：
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作者：
C. Hill;Georgia M. Cook;S. J. Spratley;S. C. Graham;J. Deane
鞘脂是细胞膜的重要组成部分，其合成或降解的缺陷会导致严重的人类疾病。溶酶体中鞘脂的有效降解需要脂质结合皂苷蛋白和水解酶。鞘糖脂半乳糖脑苷脂是髓鞘的主要脂质成分，可被水解酶 β-半乳糖脑苷脂酶 (GALC) 降解。这种酶需要皂苷 SapA 来进行脂质加工，而这些蛋白质中的任何一种的缺陷都会导致严重的神经退行性疾病，即克拉伯病。在这里，我们展示了鞘糖脂加工复合物的结构，揭示了 SapA 和 GALC 如何形成异四聚体，并具有连接酶活性位点和 SapA 疏水腔的开放通道。这种结构定义了可溶性水解酶如何将这些必需脂质的极性糖基头基从其疏水性神经酰胺尾部裂解下来。此外，这种相互作用的分子细节揭示了皂苷与水解酶结合的特异性是如何编码的。
Sphingolipids are essential components of cellular membranes and defects in their synthesis or degradation cause severe human diseases. The efficient degradation of sphingolipids in the lysosome requires lipid-binding saposin proteins and hydrolytic enzymes. The glycosphingolipid galactocerebroside is the primary lipid component of the myelin sheath and is degraded by the hydrolase β-galactocerebrosidase (GALC). This enzyme requires the saposin SapA for lipid processing and defects in either of these proteins causes a severe neurodegenerative disorder, Krabbe disease. Here we present the structure of a glycosphingolipid-processing complex, revealing how SapA and GALC form a heterotetramer with an open channel connecting the enzyme active site to the SapA hydrophobic cavity. This structure defines how a soluble hydrolase can cleave the polar glycosyl headgroups of these essential lipids from their hydrophobic ceramide tails. Furthermore, the molecular details of this interaction reveal how specificity of saposin binding to hydrolases is encoded.