Mechanism of glucocerebrosidase activation and dysfunction in Gaucher disease unraveled by molecular dynamics and deep learning
The lysosomal enzyme glucocerebrosidase-1 (GCase) catalyzes the cleavage of a major glycolipid glucosylceramide into glucose and ceramide. The absence of fully functional GCase leads to the accumulation of its lipid substrates in lysosomes, causing Gaucher disease, an autosomal recessive disorder that displays profound genotype–phenotype nonconcordance. More than 250 disease-causing mutations inGBA1, the gene encoding GCase, have been discovered, although only one of these, N370S, causes 70% of disease. In this work, we have used a knowledge-based docking protocol that considers experimental data of protein–protein binding to generate a complex between GCase and its known facilitator protein saposin C (SAPC). Multiscale molecular-dynamics simulations were used to study lipid self-assembly, membrane insertion, and the dynamics of the interactions between different components of the complex. Deep learning was applied to propose a model that explains the mechanism of GCase activation, which requires SAPC. Notably, we find that conformational changes in the loops at the entrance of the substrate-binding site are stabilized by direct interactions with SAPC and that the loss of such interactions induced by N370S and another common mutation, L444P, result in destabilization of the complex and reduced GCase activation. Our results provide an atomistic-level explanation for GCase activation and the precise mechanism through which N370S and L444P cause Gaucher disease.
- Research Organization:
- Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
- Sponsoring Organization:
- National Institutes of Health (NIH); USDOE
- Grant/Contract Number:
- AC05-00OR22725
- OSTI ID:
- 1511949
- Journal Information:
- Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, Issue 11; ISSN 0027-8424
- Publisher:
- National Academy of Sciences, Washington, DC (United States)Copyright Statement
- Country of Publication:
- United States
- Language:
- English
Web of Science
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