Insights into Krabbe disease from structures of galactocerebrosidase.

[krabbe disease]

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 .