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| | <StructureSection load='6v7n' size='340' side='right'caption='[[6v7n]], [[Resolution|resolution]] 2.62Å' scene=''> | | <StructureSection load='6v7n' size='340' side='right'caption='[[6v7n]], [[Resolution|resolution]] 2.62Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6v7n]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6V7N OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6V7N FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6v7n]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6V7N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6V7N FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.62Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">LIPA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Sterol_esterase Sterol esterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.13 3.1.1.13] </span></td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6v7n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v7n OCA], [https://pdbe.org/6v7n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6v7n RCSB], [https://www.ebi.ac.uk/pdbsum/6v7n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6v7n ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6v7n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v7n OCA], [http://pdbe.org/6v7n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6v7n RCSB], [http://www.ebi.ac.uk/pdbsum/6v7n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6v7n ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/LICH_HUMAN LICH_HUMAN]] NON RARE IN EUROPE: Heterozygous familial hypercholesterolemia;Cholesteryl ester storage disease;Wolman disease. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/LICH_HUMAN LICH_HUMAN] NON RARE IN EUROPE: Heterozygous familial hypercholesterolemia;Cholesteryl ester storage disease;Wolman disease. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/LICH_HUMAN LICH_HUMAN]] Catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins to generate free fatty acids and cholesterol.<ref>PMID:15269241</ref> <ref>PMID:1718995</ref> <ref>PMID:7204383</ref> <ref>PMID:8112342</ref> <ref>PMID:9633819</ref> | + | [https://www.uniprot.org/uniprot/LICH_HUMAN LICH_HUMAN] Catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins to generate free fatty acids and cholesterol.<ref>PMID:15269241</ref> <ref>PMID:1718995</ref> <ref>PMID:7204383</ref> <ref>PMID:8112342</ref> <ref>PMID:9633819</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Sterol esterase]]
| + | [[Category: Han S]] |
| - | [[Category: Han, S]] | + | |
| - | [[Category: Cholesteryl ester storage disease]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Lysosomal acid lipase]]
| + | |
| Structural highlights
Disease
LICH_HUMAN NON RARE IN EUROPE: Heterozygous familial hypercholesterolemia;Cholesteryl ester storage disease;Wolman disease. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
Function
LICH_HUMAN Catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins to generate free fatty acids and cholesterol.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Lysosomal acid lipase (LAL) is a serine hydrolase which hydrolyzes cholesteryl ester and triglycerides delivered to the lysosomes into free cholesterol and fatty acids. LAL deficiency due to mutations in the LAL gene (LIPA) results in accumulation of triglycerides and cholesterol esters in various tissues of the body leading to pathological conditions such as Wolman's disease (WD) and Cholesteryl ester storage disease (CESD). Here we present the first crystal structure of recombinant human LAL to 2.6 A resolution in its closed form. The crystal structure was enabled by mutating three of the six potential glycosylation sites. The overall structure of human LAL (HLAL) closely resembles that of the evolutionarily related human gastric lipase (HGL). It consists of a core domain belonging to the classical alpha/beta 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 (DGL), lid open form and HLAL to gain insights and speculated a possible role of the human mutant, H274Y, leading to CESD.
Crystal Structure of human Lysosomal Acid Lipase and its Implications in Cholesteryl Ester Storage Disease (CESD).,Rajamohan F, Reyes AR, Tu M, Nedoma NL, Hoth LR, Schwaid AG, Kurumbail RG, Ward J, Han S J Lipid Res. 2020 Jun 1. pii: jlr.RA120000748. doi: 10.1194/jlr.RA120000748. PMID:32482718[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zschenker O, Oezden D, Ameis D. Lysosomal acid lipase as a preproprotein. J Biochem. 2004 Jul;136(1):65-72. doi: 10.1093/jb/mvh093. PMID:15269241 doi:http://dx.doi.org/10.1093/jb/mvh093
- ↑ Anderson RA, Sando GN. Cloning and expression of cDNA encoding human lysosomal acid lipase/cholesteryl ester hydrolase. Similarities to gastric and lingual lipases. J Biol Chem. 1991 Nov 25;266(33):22479-84. PMID:1718995
- ↑ Warner TG, Dambach LM, Shin JH, O'Brien JS. Purification of the lysosomal acid lipase from human liver and its role in lysosomal lipid hydrolysis. J Biol Chem. 1981 Mar 25;256(6):2952-7. PMID:7204383
- ↑ Ameis D, Merkel M, Eckerskorn C, Greten H. Purification, characterization and molecular cloning of human hepatic lysosomal acid lipase. Eur J Biochem. 1994 Feb 1;219(3):905-14. PMID:8112342
- ↑ Ries S, Buchler C, Schindler G, Aslanidis C, Ameis D, Gasche C, Jung N, Schambach A, Fehringer P, Vanier MT, Belli DC, Greten H, Schmitz G. Different missense mutations in histidine-108 of lysosomal acid lipase cause cholesteryl ester storage disease in unrelated compound heterozygous and hemizygous individuals. Hum Mutat. 1998;12(1):44-51. PMID:9633819 doi:<44::AID-HUMU7>3.0.CO;2-O http://dx.doi.org/10.1002/(SICI)1098-1004(1998)12:1<44::AID-HUMU7>3.0.CO;2-O
- ↑ Rajamohan F, Reyes AR, Tu M, Nedoma NL, Hoth LR, Schwaid AG, Kurumbail RG, Ward J, Han S. Crystal Structure of human Lysosomal Acid Lipase and its Implications in Cholesteryl Ester Storage Disease (CESD). J Lipid Res. 2020 Jun 1. pii: jlr.RA120000748. doi: 10.1194/jlr.RA120000748. PMID:32482718 doi:http://dx.doi.org/10.1194/jlr.RA120000748
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