Title : Insights into
Krabbe disease from structures of
galactocerebrosidase
Abstract :
- Krabbe disease is a devastating neurodegenerative disease characterized by widespread demyelination that is caused by defects in the enzyme galactocerebrosidase ( GALC )
- Disease-causing mutations have been identified throughout the GALC gene
- However, a molecular understanding of the effect of these mutations has been hampered by the lack of structural data for this enzyme
- Here we present the crystal structures of GALC and the GALC-product complex, revealing a novel domain architecture with a previously uncharacterized lectin domain not observed in other hydrolases
- All three domains of GALC contribute residues to the substrate-binding pocket, and disease-causing mutations are widely distributed throughout the protein
- Our structures provide an essential insight into the diverse effects of pathogenic mutations on GALC function in human Krabbe variants and a compelling explanation for the severity of many mutations associated with fatal infantile disease
- The localization of disease-associated mutations in the structure of GALC will facilitate identification of those patients that would be responsive to pharmacological chaperone therapies
- Furthermore, our structure provides the atomic framework for the design of such drugs