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| - | [[Image:2oxe.gif|left|200px]] | |
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| - | <!-- | + | ==Structure of the Human Pancreatic Lipase-related Protein 2== |
| - | The line below this paragraph, containing "STRUCTURE_2oxe", creates the "Structure Box" on the page.
| + | <StructureSection load='2oxe' size='340' side='right'caption='[[2oxe]], [[Resolution|resolution]] 2.80Å' scene=''> |
| - | You may change the PDB parameter (which sets the PDB file loaded into the applet) | + | == Structural highlights == |
| - | or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
| + | <table><tr><td colspan='2'>[[2oxe]] 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=2OXE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2OXE FirstGlance]. <br> |
| - | or leave the SCENE parameter empty for the default display.
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8Å</td></tr> |
| - | --> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| - | {{STRUCTURE_2oxe| PDB=2oxe | SCENE= }}
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2oxe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2oxe OCA], [https://pdbe.org/2oxe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2oxe RCSB], [https://www.ebi.ac.uk/pdbsum/2oxe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2oxe ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/LIPR2_HUMAN LIPR2_HUMAN] Lipase with broad substrate specificity. Can hydrolyze both phospholipids and galactolipids. Acts preferentially on monoglycerides, phospholipids and galactolipids. Contributes to milk fat hydrolysis.<ref>PMID:19824014</ref> <ref>PMID:20083229</ref> <ref>PMID:18702514</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ox/2oxe_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2oxe ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Access to the active site of pancreatic lipase (PL) is controlled by a surface loop, the lid, which normally undergoes conformational changes only upon addition of lipids or amphiphiles. Structures of PL with their lids in the open and functional conformation have required cocrystallization with amphiphiles. Here we report two crystal structures of wild-type and unglycosylated human pancreatic lipase-related protein 2 (HPLRP2) with the lid in an open conformation in the absence of amphiphiles. These structures solved independently are strikingly similar, with some residues of the lid being poorly defined in the electron-density map. The open conformation of the lid is however different from that previously observed in classical liganded PL, suggesting different kinetic properties for HPLRP2. Here we show that the HPLRP2 is directly inhibited by E600, does not present interfacial activation, and acts preferentially on substrates forming monomers or small aggregates (micelles) dispersed in solution like monoglycerides, phospholipids and galactolipids, whereas classical PL displays reverse properties and a high specificity for unsoluble substrates like triglycerides and diglycerides forming oil-in-water interfaces. These biochemical properties imply that the lid of HPLRP2 is likely to spontaneously adopt in solution the open conformation observed in the crystal structure. This open conformation generates a large cavity capable of accommodating the digalactose polar head of galactolipids, similar to that previously observed in the active site of the guinea pig PLRP2, but absent from the classical PL. Most of the structural and kinetic properties of HPLRP2 were found to be different from those of rat PLRP2, the structure of which was previously obtained with the lid in a closed conformation. Our findings illustrate the essential role of the lid in determining the substrate specificity and the mechanism of action of lipases. |
| | | | |
| - | '''Structure of the Human Pancreatic Lipase-related Protein 2'''
| + | Structure of human pancreatic lipase-related protein 2 with the lid in an open conformation.,Eydoux C, Spinelli S, Davis TL, Walker JR, Seitova A, Dhe-Paganon S, De Caro A, Cambillau C, Carriere F Biochemistry. 2008 Sep 9;47(36):9553-64. Epub 2008 Aug 15. PMID:18702514<ref>PMID:18702514</ref> |
| | | | |
| - | | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | ==Overview==
| + | </div> |
| - | Human pancreatic lipase-related protein 2 (HPLRP2) was found to be expressed in the pancreas, but its biochemical properties were not investigated in detail. A recombinant HPLRP2 was produced in insect cells and the yeast Pichia pastoris and purified by cation exchange chromatography. Its substrate specificity was investigated using pH-stat and monomolecular film techniques and various lipid substrates (triglycerides, diglycerides, phospholipids, and galactolipids). Lipase activity of HPLRP2 on trioctanoin was inhibited by bile salts and poorly restored by adding colipase. In vivo, HPLRP2 therefore seems unlikely to show any lipase activity on dietary fat. In human pancreatic lipase (HPL), residues R256, D257, Y267, and K268 are involved in the stabilization of the open conformation of the lid domain, which interacts with colipase. These residues are not conserved in HPLRP2. When the corresponding mutations (R256G, D257G, Y267F, and K268E) are introduced into HPL, the effects of colipase are drastically reduced in the presence of bile salts. This may explain why colipase has such weak effects on HPLRP2. HPLRP2 displayed a very low level of activity on phospholipid micelles and monomolecular films. Its activity on monogalactosyldiglyceride monomolecular film, which was much higher, was similar to the activity of guinea pig pancreatic lipase related-protein 2, which shows the highest galactolipase activity ever measured. The physiological role of HPLRP2 suggested by the present results is the digestion of galactolipids, the most abundant lipids occurring in plant cells, and therefore, in the vegetables that are part of the human diet.
| + | <div class="pdbe-citations 2oxe" style="background-color:#fffaf0;"></div> |
| - | | + | == References == |
| - | ==About this Structure== | + | <references/> |
| - | 2OXE is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OXE OCA].
| + | __TOC__ |
| - | | + | </StructureSection> |
| - | ==Reference== | + | |
| - | Human pancreatic lipase-related protein 2 is a galactolipase., Sias B, Ferrato F, Grandval P, Lafont D, Boullanger P, De Caro A, Leboeuf B, Verger R, Carriere F, Biochemistry. 2004 Aug 10;43(31):10138-48. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15287741 15287741]
| + | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Triacylglycerol lipase]]
| + | [[Category: Arrowsmith CH]] |
| - | [[Category: Arrowsmith, C H.]] | + | [[Category: Bochkarev A]] |
| - | [[Category: Bochkarev, A.]] | + | [[Category: Butler-Cole C]] |
| - | [[Category: Butler-Cole, C.]] | + | [[Category: Davis T]] |
| - | [[Category: Davis, T.]] | + | [[Category: Dhe-Paganon S]] |
| - | [[Category: Dhe-Paganon, S.]] | + | [[Category: Edwards AM]] |
| - | [[Category: Edwards, A M.]] | + | [[Category: Finerty Jr PJ]] |
| - | [[Category: Jr., P J.Finerty.]] | + | [[Category: Kozieradzki I]] |
| - | [[Category: Kozieradzki, I.]] | + | [[Category: Seitova A]] |
| - | [[Category: SGC, Structural Genomics Consortium.]]
| + | [[Category: Sundstrom M]] |
| - | [[Category: Seitova, A.]] | + | [[Category: Walker JR]] |
| - | [[Category: Sundstrom, M.]] | + | [[Category: Weigelt J]] |
| - | [[Category: Walker, J R.]] | + | |
| - | [[Category: Weigelt, J.]] | + | |
| - | [[Category: Glycoprotein]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Lipid degradation]]
| + | |
| - | [[Category: Pancreatic lipase]]
| + | |
| - | [[Category: Sgc]]
| + | |
| - | [[Category: Structural genomics consortium]]
| + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 11:52:08 2008''
| + | |
| Structural highlights
Function
LIPR2_HUMAN Lipase with broad substrate specificity. Can hydrolyze both phospholipids and galactolipids. Acts preferentially on monoglycerides, phospholipids and galactolipids. Contributes to milk fat hydrolysis.[1] [2] [3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Access to the active site of pancreatic lipase (PL) is controlled by a surface loop, the lid, which normally undergoes conformational changes only upon addition of lipids or amphiphiles. Structures of PL with their lids in the open and functional conformation have required cocrystallization with amphiphiles. Here we report two crystal structures of wild-type and unglycosylated human pancreatic lipase-related protein 2 (HPLRP2) with the lid in an open conformation in the absence of amphiphiles. These structures solved independently are strikingly similar, with some residues of the lid being poorly defined in the electron-density map. The open conformation of the lid is however different from that previously observed in classical liganded PL, suggesting different kinetic properties for HPLRP2. Here we show that the HPLRP2 is directly inhibited by E600, does not present interfacial activation, and acts preferentially on substrates forming monomers or small aggregates (micelles) dispersed in solution like monoglycerides, phospholipids and galactolipids, whereas classical PL displays reverse properties and a high specificity for unsoluble substrates like triglycerides and diglycerides forming oil-in-water interfaces. These biochemical properties imply that the lid of HPLRP2 is likely to spontaneously adopt in solution the open conformation observed in the crystal structure. This open conformation generates a large cavity capable of accommodating the digalactose polar head of galactolipids, similar to that previously observed in the active site of the guinea pig PLRP2, but absent from the classical PL. Most of the structural and kinetic properties of HPLRP2 were found to be different from those of rat PLRP2, the structure of which was previously obtained with the lid in a closed conformation. Our findings illustrate the essential role of the lid in determining the substrate specificity and the mechanism of action of lipases.
Structure of human pancreatic lipase-related protein 2 with the lid in an open conformation.,Eydoux C, Spinelli S, Davis TL, Walker JR, Seitova A, Dhe-Paganon S, De Caro A, Cambillau C, Carriere F Biochemistry. 2008 Sep 9;47(36):9553-64. Epub 2008 Aug 15. PMID:18702514[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Berton A, Sebban-Kreuzer C, Rouvellac S, Lopez C, Crenon I. Individual and combined action of pancreatic lipase and pancreatic lipase-related proteins 1 and 2 on native versus homogenized milk fat globules. Mol Nutr Food Res. 2009 Dec;53(12):1592-602. doi: 10.1002/mnfr.200800563. PMID:19824014 doi:http://dx.doi.org/10.1002/mnfr.200800563
- ↑ Amara S, Barouh N, Lecomte J, Lafont D, Robert S, Villeneuve P, De Caro A, Carriere F. Lipolysis of natural long chain and synthetic medium chain galactolipids by pancreatic lipase-related protein 2. Biochim Biophys Acta. 2010 Apr;1801(4):508-16. doi: 10.1016/j.bbalip.2010.01.003., Epub 2010 Jan 18. PMID:20083229 doi:http://dx.doi.org/10.1016/j.bbalip.2010.01.003
- ↑ Eydoux C, Spinelli S, Davis TL, Walker JR, Seitova A, Dhe-Paganon S, De Caro A, Cambillau C, Carriere F. Structure of human pancreatic lipase-related protein 2 with the lid in an open conformation. Biochemistry. 2008 Sep 9;47(36):9553-64. Epub 2008 Aug 15. PMID:18702514 doi:10.1021/bi8005576
- ↑ Eydoux C, Spinelli S, Davis TL, Walker JR, Seitova A, Dhe-Paganon S, De Caro A, Cambillau C, Carriere F. Structure of human pancreatic lipase-related protein 2 with the lid in an open conformation. Biochemistry. 2008 Sep 9;47(36):9553-64. Epub 2008 Aug 15. PMID:18702514 doi:10.1021/bi8005576
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