Cambridge Institute for Medical Research, Department of Pathology, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK.
Nat Commun. 2018 Jan 11;9(1):151. doi: 10.1038/s41467-017-02361-y.
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 provide an illustration for how specificity of saposin binding to hydrolases is encoded.
鞘脂是细胞膜的重要组成部分，其合成或降解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的神经鞘脂激活蛋白和水解酶。半乳糖脑苷脂是髓鞘的主要脂质成分，由水解酶β-半乳糖脑苷脂酶（GALC）降解。该酶需要神经鞘脂激活蛋白 SapA 进行脂质加工，这两种蛋白质的缺陷都会导致一种严重的神经退行性疾病——克雅氏病。本文呈现了一个糖脂加工复合物的结构，揭示了 SapA 和 GALC 如何形成一个具有开放通道的异四聚体，将酶的活性位点与 SapA 的疏水性腔连接起来。该结构定义了一种可溶性水解酶如何能够从其疏水性神经酰胺尾部将这些必需脂质的极性糖基头部基团切断。此外，这种相互作用的分子细节为神经鞘脂激活蛋白与水解酶结合的特异性如何被编码提供了一个例证。
