Heger L, Ankermann P, Socher E (2025)
Publication Type: Journal article
Publication year: 2025
Book Volume: 26
Pages Range: 8647
Issue: 17
DOI: 10.3390/ijms26178647
Krabbe disease is a rare and severe lysosomal disorder affecting the white matter of the central and peripheral nervous system. It is characterized by neurodegeneration, with the most common form being infantile Krabbe disease, typically diagnosed within the first year of life. This autosomal-recessive disease is caused by mutations in the GALC gene, which encodes the lysosomal enzyme β-galactocerebrosidase. This study focuses on a β-galactocerebrosidase variant, with Thr112Ala identified as a homozygous mutation in a patient with infantile Krabbe disease. To understand the structural effects of this mutation, we conducted all-atom molecular dynamics simulations of both the mutant and wild-type (wt) enzymes at cytosolic (pH 7.0) and lysosomal pH (pH 4.5), as β-galactocerebrosidase is localized in the lysosome. The results showed differences in protein flexibility, the hydrogen bond network, and the stability of secondary structure elements between the wild type and mutant enzymes. Additionally, the mutation affected the size of the substrate-binding pocket at lysosomal pH, even though the mutation site is not part of the active/binding site of the enzyme. These findings provide valuable insights into how the mutation impacts the structure of β-galactocerebrosidase in the lysosomal environment, contributing to the understanding of Krabbe disease’s molecular mechanisms.
APA:
Heger, L., Ankermann, P., & Socher, E. (2025). Molecular Characterization of the GALC Mutation Thr112Ala Causing Krabbe Disease. International Journal of Molecular Sciences, 26, 8647. https://doi.org/10.3390/ijms26178647
MLA:
Heger, Lukas, Piet Ankermann, and Eileen Socher. "Molecular Characterization of the GALC Mutation Thr112Ala Causing Krabbe Disease." International Journal of Molecular Sciences 26 (2025): 8647.
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