RT Journal Article
SR Electronic
T1 The mechanism of sphingolipid processing revealed by a GALC-SapA complex structure
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 112029
DO 10.1101/112029
A1 Chris H. Hill
A1 Georgia M. Cook
A1 Samantha J. Spratley
A1 Stephen C. Graham
A1 Janet E. Deane
YR 2017
UL http://biorxiv.org/content/early/2017/02/27/112029.abstract
AB 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.