Crystal structure of human lysosomal acid lipase and its implications in cholesteryl ester storage disease[S]

• Published in: Journal of lipid research Vol. 61; no. 8; pp. 1192 - 1202
• Main Authors: Rajamohan, Francis, Reyes, Allan R., Tu, Meihua, Nedoma, Nicole L., Hoth, Lise R., Schwaid, Adam G., Kurumbail, Ravi G., Ward, Jessica, Han, Seungil
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-08-2020; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Cholesterol Ester Storage Disease - enzymology; Cholesterol Ester Storage Disease - genetics; Crystallography, X-Ray; Glycosylation; Humans; lipid metabolism; lysosomal acid lipase deficiency; Models, Molecular; molecular dynamic simulations; Mutation; protein aggregation; Protein Domains; Sterol Esterase - chemistry; Sterol Esterase - genetics; Sterol Esterase - metabolism; Wolman's disease; molecular dynamic simulations; Wolman's disease; protein aggregation; lysosomal acid lipase deficiency; lipid metabolism; Wolman’s disease
• ISSN: 0022-2275; 1539-7262; 1539-7262
• DOI: 10.1194/jlr.RA120000748

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, 238NLCFLLC244, 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.