Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36
Neculai D, Schwake M, Ravichandran M, Zunke F, Collins RF, Peters J, Neculai M, Plumb J, Loppnau P, Pizarro JC, Seitova A, et al. (2013)
Nature 504(7478): 172-176.
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Autor*in
Neculai, Dante;
Schwake, MichaelUniBi 
;
Ravichandran, Mani;
Zunke, Friederike;
Collins, Richard F.;
Peters, Judith;
Neculai, Mirela;
Plumb, Jonathan;
Loppnau, Peter;
Pizarro, Juan Carlos;
Seitova, Alma;
Trimble, William S.
Alle
;
Ravichandran, Mani;
Zunke, Friederike;
Collins, Richard F.;
Peters, Judith;
Neculai, Mirela;
Plumb, Jonathan;
Loppnau, Peter;
Pizarro, Juan Carlos;
Seitova, Alma;
Trimble, William S.
Alle
Einrichtung
Abstract / Bemerkung
Members of the CD36 superfamily of scavenger receptor proteins are important regulators of lipid metabolism and innate immunity. They recognize normal and modified lipoproteins, as well as pathogen-associated molecular patterns. The family consists of three members: SR-BI (which delivers cholesterol to the liver and steroidogenic organs and is a co-receptor for hepatitis C virus), LIMP-2/LGP85 (which mediates lysosomal delivery of beta-glucocerebrosidase and serves as a receptor for enterovirus 71 and coxsackieviruses) and CD36 (a fatty-acid transporter and receptor for phagocytosis of effete cells and Plasmodium-infected erythrocytes). Notably, CD36 is also a receptor for modified lipoproteins and beta-amyloid, and has been implicated in the pathogenesis of atherosclerosis and of Alzheimer's disease(1). Despite their prominent roles in health and disease, understanding the function and abnormalities of the CD36 family members has been hampered by the paucity of information about their structure. Here we determine the crystal structure of LIMP-2 and infer, by homology modelling, the structure of SR-BI and CD36. LIMP-2 shows a helical bundle where beta-glucocerebrosidase binds, and where ligands are most likely to bind to SR-BI and CD36. Remarkably, the crystal structure also shows the existence of a large cavity that traverses the entire length of the molecule. Mutagenesis of SR-BI indicates that the cavity serves as a tunnel through which cholesterol(esters) are delivered from the bound lipoprotein to the outer leaflet of the plasma membrane. We provide evidence supporting a model(2) whereby lipidic constituents of the ligands attached to the receptor surface are handed off to the membrane through the tunnel, accounting for the selective lipid transfer characteristic of SR-BI and CD36.
Erscheinungsjahr
2013
Zeitschriftentitel
Nature
Band
504
Ausgabe
7478
Seite(n)
172-176
ISSN
0028-0836
eISSN
1476-4687
Page URI
https://pub.uni-bielefeld.de/record/2645175
Zitieren
Neculai D, Schwake M, Ravichandran M, et al. Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36. Nature. 2013;504(7478):172-176.
Neculai, D., Schwake, M., Ravichandran, M., Zunke, F., Collins, R. F., Peters, J., Neculai, M., et al. (2013). Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36. Nature, 504(7478), 172-176. doi:10.1038/nature12684
Neculai, Dante, Schwake, Michael, Ravichandran, Mani, Zunke, Friederike, Collins, Richard F., Peters, Judith, Neculai, Mirela, et al. 2013. “Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36”. Nature 504 (7478): 172-176.
Neculai, D., Schwake, M., Ravichandran, M., Zunke, F., Collins, R. F., Peters, J., Neculai, M., Plumb, J., Loppnau, P., Pizarro, J. C., et al. (2013). Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36. Nature 504, 172-176.
Neculai, D., et al., 2013. Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36. Nature, 504(7478), p 172-176.
D. Neculai, et al., “Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36”, Nature, vol. 504, 2013, pp. 172-176.
Neculai, D., Schwake, M., Ravichandran, M., Zunke, F., Collins, R.F., Peters, J., Neculai, M., Plumb, J., Loppnau, P., Pizarro, J.C., Seitova, A., Trimble, W.S., Saftig, P., Grinstein, S., Dhe-Paganon, S.: Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36. Nature. 504, 172-176 (2013).
Neculai, Dante, Schwake, Michael, Ravichandran, Mani, Zunke, Friederike, Collins, Richard F., Peters, Judith, Neculai, Mirela, Plumb, Jonathan, Loppnau, Peter, Pizarro, Juan Carlos, Seitova, Alma, Trimble, William S., Saftig, Paul, Grinstein, Sergio, and Dhe-Paganon, Sirano. “Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36”. Nature 504.7478 (2013): 172-176.
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PDB
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x-ray diffraction (PDB: 4f7b)
Protein structure name: structure of the lysosomal domain of limp-2
Public wwPDB file in PDB format
Protein structure name: structure of the lysosomal domain of limp-2
Public wwPDB file in PDB format
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Mao B, Huang S, Lu X, Sun W, Zhou Y, Pan X, Yu J, Lai M, Chen B, Zhou Q, Mao S, Bian G, Zhou J, Nakahata T, Ma F., Stem Cell Reports 7(5), 2016
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The lysosomal membrane protein SCAV-3 maintains lysosome integrity and adult longevity.
Li Y, Chen B, Zou W, Wang X, Wu Y, Zhao D, Sun Y, Liu Y, Chen L, Miao L, Yang C, Wang X., J Cell Biol 215(2), 2016
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Scavenger Receptor Class B, Type I, a CD36 Related Protein in Macrobrachium nipponense: Characterization, RNA Interference, and Expression Analysis with Different Dietary Lipid Sources.
Ding Z, Luo N, Kong Y, Li J, Zhang Y, Cao F, Ye J., Int J Genomics 2016(), 2016
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Ding Z, Luo N, Kong Y, Li J, Zhang Y, Cao F, Ye J., Int J Genomics 2016(), 2016
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β-oxidation and rapid metabolism, but not uptake regulate brain eicosapentaenoic acid levels.
Chen CT, Bazinet RP., Prostaglandins Leukot Essent Fatty Acids 92(), 2015
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Expression, purification and reconstitution of the C-terminal transmembrane domain of scavenger receptor BI into detergent micelles for NMR analysis.
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CD36 binds oxidized low density lipoprotein (LDL) in a mechanism dependent upon fatty acid binding.
Jay AG, Chen AN, Paz MA, Hung JP, Hamilton JA., J Biol Chem 290(8), 2015
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Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease.
Peters J, Rittger A, Weisner R, Knabbe J, Zunke F, Rothaug M, Damme M, Berkovic SF, Blanz J, Saftig P, Schwake M., Biochem Biophys Res Commun 457(3), 2015
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Peters J, Rittger A, Weisner R, Knabbe J, Zunke F, Rothaug M, Damme M, Berkovic SF, Blanz J, Saftig P, Schwake M., Biochem Biophys Res Commun 457(3), 2015
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Recent progress in molecular genetic studies on the carotenoid transport system using cocoon-color mutants of the silkworm.
Tsuchida K, Sakudoh T., Arch Biochem Biophys 572(), 2015
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Intestinal absorption of vitamin D: from the meal to the enterocyte.
Reboul E., Food Funct 6(2), 2015
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Scavenger receptor B protects shrimp from bacteria by enhancing phagocytosis and regulating expression of antimicrobial peptides.
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Estrogens prevent metabolic dysfunctions induced by circadian disruptions in female mice.
Zhu L, Zou F, Yang Y, Xu P, Saito K, Othrell Hinton A, Yan X, Ding H, Wu Q, Fukuda M, Sun Z, Tong Q, Xu Y., Endocrinology 156(6), 2015
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Discovery of bisamide-heterocycles as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake.
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Role of LIMP-2 in the intracellular trafficking of β-glucosidase in different human cellular models.
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A novel assay uncovers an unexpected role for SR-BI in LDL transcytosis.
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What does procollagen C-endopeptidase enhancer protein 2 have to do with HDL-cholesteryl ester uptake? Or how I learned to stop worrying and love reverse cholesterol transport?
Sorci-Thomas MG, Pollard RD, Thomas MJ., Curr Opin Lipidol 26(5), 2015
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Sorci-Thomas MG, Pollard RD, Thomas MJ., Curr Opin Lipidol 26(5), 2015
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Nanoparticle Targeting and Cholesterol Flux Through Scavenger Receptor Type B-1 Inhibits Cellular Exosome Uptake.
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Structure-function of CD36 and importance of fatty acid signal transduction in fat metabolism.
Pepino MY, Kuda O, Samovski D, Abumrad NA., Annu Rev Nutr 34(), 2014
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Molecular mechanisms of cellular cholesterol efflux.
Phillips MC., J Biol Chem 289(35), 2014
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CD36 and malaria: friends or foes? A decade of data provides some answers.
Cabrera A, Neculai D, Kain KC., Trends Parasitol 30(9), 2014
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Protein sorting at the trans-Golgi network.
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The cellular receptor for enterovirus 71.
Liu Y, Rossmann MG., Protein Cell 5(9), 2014
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SR-BI/CD36 chimeric receptors define extracellular subdomains of SR-BI critical for cholesterol transport.
Kartz GA, Holme RL, Nicholson K, Sahoo D., Biochemistry 53(39), 2014
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Cyclophilin A associates with enterovirus-71 virus capsid and plays an essential role in viral infection as an uncoating regulator.
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LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance.
Rothaug M, Zunke F, Mazzulli JR, Schweizer M, Altmeppen H, Lüllmann-Rauch R, Kallemeijn WW, Gaspar P, Aerts JM, Glatzel M, Saftig P, Krainc D, Schwake M, Blanz J., Proc Natl Acad Sci U S A 111(43), 2014
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Polyunsaturated fatty acids and their metabolites in brain function and disease.
Bazinet RP, Layé S., Nat Rev Neurosci 15(12), 2014
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Mipu1 overexpression protects macrophages from oxLDL-induced foam cell formation and cell apoptosis.
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