Hill, Chris H orcid.org/0000-0001-7037-0611, Cook, Georgia M, Fawke, Stuart et al. (2 more authors) (2018) The mechanism of glycosphingolipid degradation revealed by a GALC-SapA complex structure. Nature Communications. 151. ISSN 2041-1723
Abstract
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2017 |
Keywords: | Cell Line,Ceramides/metabolism,Galactosylceramidase/metabolism,Glycosphingolipids/metabolism,HEK293 Cells,Humans,Hydrophobic and Hydrophilic Interactions,Protein Binding/genetics,Protein Structure, Tertiary,Saposins/genetics |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 22 Oct 2021 11:20 |
Last Modified: | 25 Mar 2025 00:12 |
Published Version: | https://doi.org/10.1038/s41467-017-02361-y |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1038/s41467-017-02361-y |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:179533 |
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Description: The mechanism of glycosphingolipid degradation revealed by a GALC-SapA complex structure
Licence: CC-BY 2.5