Download MendeleyInsights Into Krabbe Disease from Structures of Galactocerebrosidase.
Deane, J.E., Graham, S.C., Kim, N.N., Stein, P.E., Mcnair, R., Cachon-Gonzalez, M.B., Cox, T.M., Read, R.J.(2011) Proc Natl Acad Sci U S A 108: 15169
- PubMed: 21876145
- DOI: https://doi.org/10.1073/pnas.1105639108
- Primary Citation of Related Structures:
3ZR5, 3ZR6 - PubMed 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.
Organizational Affiliation:
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, United Kingdom. [email protected]
