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Crystal structure of human lysosomal acid lipase and its implications in cholesteryl ester storage disease
Lysosomal acid lipase (LAL) is a serine hydrolase that hydrolyzes cholesteryl ester (CE) and TGs delivered to the lysosomes into free cholesterol and fatty acids. LAL deficiency due to mutations in the LAL gene (LIPA) results in accumulation of TGs and cholesterol esters in various tissues of the bo...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Biochemistry and Molecular Biology
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397744/ https://www.ncbi.nlm.nih.gov/pubmed/32482718 http://dx.doi.org/10.1194/jlr.RA120000748 |
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author | Rajamohan, Francis Reyes, Allan R. Tu, Meihua Nedoma, Nicole L. Hoth, Lise R. Schwaid, Adam G. Kurumbail, Ravi G. Ward, Jessica Han, Seungil |
author_facet | Rajamohan, Francis Reyes, Allan R. Tu, Meihua Nedoma, Nicole L. Hoth, Lise R. Schwaid, Adam G. Kurumbail, Ravi G. Ward, Jessica Han, Seungil |
author_sort | Rajamohan, Francis |
collection | PubMed |
description | Lysosomal acid lipase (LAL) is a serine hydrolase that hydrolyzes cholesteryl ester (CE) and TGs delivered to the lysosomes into free cholesterol and fatty acids. LAL deficiency due to mutations in the LAL gene (LIPA) results in accumulation of TGs and cholesterol esters in various tissues of the body leading to pathological conditions such as Wolman’s disease and CE storage disease (CESD). Here, we present the first crystal structure of recombinant human LAL (HLAL) to 2.6 Å resolution in its closed form. The crystal structure was enabled by mutating three of the six potential glycosylation sites. The overall structure of HLAL closely resembles that of the evolutionarily related human gastric lipase (HGL). It consists of a core domain belonging to the classical α/β hydrolase-fold family with a classical catalytic triad (Ser-153, His-353, Asp-324), an oxyanion hole, and a “cap” domain, which regulates substrate entry to the catalytic site. Most significant structural differences between HLAL and HGL exist at the lid region. Deletion of the short helix, (238)NLCFLLC(244), at the lid region implied a possible role in regulating the highly hydrophobic substrate binding site from self-oligomerization during interfacial activation. We also performed molecular dynamic simulations of dog gastric lipase (lid-open form) and HLAL to gain insights and speculated a possible role of the human mutant, H274Y, leading to CESD. |
format | Online Article Text |
id | pubmed-7397744 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | The American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-73977442020-08-10 Crystal structure of human lysosomal acid lipase and its implications in cholesteryl ester storage disease Rajamohan, Francis Reyes, Allan R. Tu, Meihua Nedoma, Nicole L. Hoth, Lise R. Schwaid, Adam G. Kurumbail, Ravi G. Ward, Jessica Han, Seungil J Lipid Res Research Articles Lysosomal acid lipase (LAL) is a serine hydrolase that hydrolyzes cholesteryl ester (CE) and TGs delivered to the lysosomes into free cholesterol and fatty acids. LAL deficiency due to mutations in the LAL gene (LIPA) results in accumulation of TGs and cholesterol esters in various tissues of the body leading to pathological conditions such as Wolman’s disease and CE storage disease (CESD). Here, we present the first crystal structure of recombinant human LAL (HLAL) to 2.6 Å resolution in its closed form. The crystal structure was enabled by mutating three of the six potential glycosylation sites. The overall structure of HLAL closely resembles that of the evolutionarily related human gastric lipase (HGL). It consists of a core domain belonging to the classical α/β hydrolase-fold family with a classical catalytic triad (Ser-153, His-353, Asp-324), an oxyanion hole, and a “cap” domain, which regulates substrate entry to the catalytic site. Most significant structural differences between HLAL and HGL exist at the lid region. Deletion of the short helix, (238)NLCFLLC(244), at the lid region implied a possible role in regulating the highly hydrophobic substrate binding site from self-oligomerization during interfacial activation. We also performed molecular dynamic simulations of dog gastric lipase (lid-open form) and HLAL to gain insights and speculated a possible role of the human mutant, H274Y, leading to CESD. The American Society for Biochemistry and Molecular Biology 2020-08 2020-06-01 /pmc/articles/PMC7397744/ /pubmed/32482718 http://dx.doi.org/10.1194/jlr.RA120000748 Text en Copyright © 2020 Rajamohan et al. Published by The American Society for Biochemistry and Molecular Biology, Inc. http://creativecommons.org/licenses/by/4.0/ Author’s Choice—Final version open access under the terms of the Creative Commons CC-BY license. |
spellingShingle | Research Articles Rajamohan, Francis Reyes, Allan R. Tu, Meihua Nedoma, Nicole L. Hoth, Lise R. Schwaid, Adam G. Kurumbail, Ravi G. Ward, Jessica Han, Seungil Crystal structure of human lysosomal acid lipase and its implications in cholesteryl ester storage disease |
title | Crystal structure of human lysosomal acid lipase and its implications in cholesteryl ester storage disease |
title_full | Crystal structure of human lysosomal acid lipase and its implications in cholesteryl ester storage disease |
title_fullStr | Crystal structure of human lysosomal acid lipase and its implications in cholesteryl ester storage disease |
title_full_unstemmed | Crystal structure of human lysosomal acid lipase and its implications in cholesteryl ester storage disease |
title_short | Crystal structure of human lysosomal acid lipase and its implications in cholesteryl ester storage disease |
title_sort | crystal structure of human lysosomal acid lipase and its implications in cholesteryl ester storage disease |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397744/ https://www.ncbi.nlm.nih.gov/pubmed/32482718 http://dx.doi.org/10.1194/jlr.RA120000748 |
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