Insights into Krabbe disease from structures of galactocerebrosidase

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2011-09, Vol.108 (37), p.15169-15173
Main Authors: Deane, Janet E., Graham, Stephen C., Kim, Nee Na, Stein, Penelope E., McNair, Rosamund, Cachón-González, M. Begoña, Cox, Timothy M., Read, Randy J.
Format: Article
Language:English
Subjects:
Active sites
Animals
Binding Sites
Biological Sciences
Crystallography, X-Ray
Enzymes
Galactosylceramidase - chemistry
Galactosylceramidase - genetics
Galactosylceramides - chemistry
Galactosylceramides - metabolism
Genes
Genetic mutation
Globoid cell leukodystrophy
HEK293 Cells
Humans
Lectins
Leukodystrophy, Globoid Cell - enzymology
Leukodystrophy, Globoid Cell - genetics
Lipids
Lysosomes
Mice
Models, Molecular
Molecules
Mutation
Mutation - genetics
Neurodegeneration
Neurological disorders
Pharmacology
Protein Structure, Secondary
Sphingolipids
Substrate Specificity
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Description
Summary: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 substratebinding 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1105639108