5nxb

From Proteopedia

Mouse galactocerebrosidase in complex with saposin A

Structural highlights

5nxb is a 4 chain structure with sequence from Mus musculus. This structure supersedes the now removed PDB entry 5n8k. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.6Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GALC_MOUSE Defects in Galc are the cause of the 'twitcher' phenotype; an autosomal recessive leukodystrophy similar to the human disease (Krabbe disease). This deficiency results in the insufficient catabolism of several galactolipids that are important in the production of normal myelin.

Function

GALC_MOUSE Hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Enzyme with very low activity responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon.^[1]

Publication Abstract from PubMed

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 beta-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.

The mechanism of glycosphingolipid degradation revealed by a GALC-SapA complex structure.,Hill CH, Cook GM, Spratley SJ, Fawke S, Graham SC, Deane JE Nat Commun. 2018 Jan 11;9(1):151. doi: 10.1038/s41467-017-02361-y. PMID:29323104^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Sakai N, Inui K, Tatsumi N, Fukushima H, Nishigaki T, Taniike M, Nishimoto J, Tsukamoto H, Yanagihara I, Ozono K, Okada S. Molecular cloning and expression of cDNA for murine galactocerebrosidase and mutation analysis of the twitcher mouse, a model of Krabbe's disease. J Neurochem. 1996 Mar;66(3):1118-24. PMID:8769874
↑ Hill CH, Cook GM, Spratley SJ, Fawke S, Graham SC, Deane JE. The mechanism of glycosphingolipid degradation revealed by a GALC-SapA complex structure. Nat Commun. 2018 Jan 11;9(1):151. doi: 10.1038/s41467-017-02361-y. PMID:29323104 doi:http://dx.doi.org/10.1038/s41467-017-02361-y