globalchange  > 气候变化与战略
DOI: 10.1073/pnas.1818411116
论文题名:
Mechanism of glucocerebrosidase activation and dysfunction in Gaucher disease unraveled by molecular dynamics and deep learning
作者: Romero R.; Ramanathan A.; Yuen T.; Bhowmik D.; Mathew M.; Munshi L.B.; Javaid S.; Bloch M.; Lizneva D.; Rahimova A.; Khan A.; Taneja C.; Kim S.-M.; Sun L.; New M.I.; Haider S.; Zaidi M.
刊名: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
出版年: 2019
卷: 116, 期:11
起始页码: 5086
结束页码: 5095
语种: 英语
英文关键词: Gene mutations ; Lysosomal storage disease ; Multiscale simulations ; Rare disease
Scopus关键词: asparagine ; glucosylceramidase ; leucine ; lipid ; proline ; protein SAPC ; serine ; sphingolipid activator protein ; unclassified drug ; glucosylceramidase ; mutant protein ; sphingolipid activator protein ; Article ; binding site ; conformational transition ; deep learning ; enzyme activation ; enzyme stability ; enzyme substrate complex ; Gaucher disease ; human ; knowledge base ; molecular docking ; molecular dynamics ; molecular mechanics ; mutational analysis ; priority journal ; protein assembly ; protein binding ; protein protein interaction ; chemistry ; enzyme activation ; enzyme active site ; enzymology ; Gaucher disease ; hydrogen bond ; metabolism ; molecular dynamics ; pathophysiology ; protein analysis ; protein secondary structure ; Catalytic Domain ; Deep Learning ; Enzyme Activation ; Gaucher Disease ; Glucosylceramidase ; Humans ; Hydrogen Bonding ; Molecular Dynamics Simulation ; Mutant Proteins ; Protein Interaction Maps ; Protein Structure, Secondary ; Saposins
英文摘要: 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 diseasecausing mutations in GBA1, the gene encoding GCase, have been discovered, although only one of these, N370S, causes 70% of disease. Here, 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 findings provide an atomistic-level explanation for GCase activation and the precise mechanism through which N370S and L444P cause Gaucher disease. © 2019 National Academy of Sciences. All Rights Reserved.
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资源类型: 期刊论文
标识符: http://119.78.100.158/handle/2HF3EXSE/163607
Appears in Collections:气候变化与战略

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作者单位: Romero, R., Department of Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, London, WC1N 1AX, United Kingdom; Ramanathan, A., Computational Science and Engineering Division, Oak Ridge National Laboratory, Oak Ridge, TN 37830, United States; Yuen, T., Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States, Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Bhowmik, D., Computational Science and Engineering Division, Oak Ridge National Laboratory, Oak Ridge, TN 37830, United States; Mathew, M., Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Munshi, L.B., Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Javaid, S., Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Bloch, M., Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Lizneva, D., Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States, Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Rahimova, A., Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States, Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Khan, A., Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Taneja, C., Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States, Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Kim, S.-M., Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States, Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Sun, L., Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States, Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; New, M.I., Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Haider, S., Department of Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, London, WC1N 1AX, United Kingdom; Zaidi, M., Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States, Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States

Recommended Citation:
Romero R.,Ramanathan A.,Yuen T.,et al. Mechanism of glucocerebrosidase activation and dysfunction in Gaucher disease unraveled by molecular dynamics and deep learning[J]. Proceedings of the National Academy of Sciences of the United States of America,2019-01-01,116(11)
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