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SCARB2

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SCARB2
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesSCARB2,AMRF, CD36L2, EPM4, HLGP85, LGP85, LIMP-2, LIMPII, SR-BII, scavenger receptor class B member 2
External IDsOMIM:602257;MGI:1196458;HomoloGene:48353;GeneCards:SCARB2;OMA:SCARB2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_005506
NM_001204255

NM_007644

RefSeq (protein)

NP_001191184
NP_005497

NP_031670

Location (UCSC)Chr 4: 76.16 – 76.23 MbChr 5: 92.59 – 92.65 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Lysosomal integral membrane protein 2 (LIMP-2)is aproteinthat in humans is encoded by theSCARB2gene.[5]LIMP-2 is expressed inbrain,heart,liver,lungandkidney,mainly in the membrane oflysosomeorganelles; however, incardiac muscle,LIMP-2 is also expressed atintercalated discs.LIMP-2 in a membraneproteininlysosomesthat functions to regulatelysosomal/endosomaltransport. Mutations in LIMP-2 have been shown to causeGaucher disease,myoclonic epilepsy,and action myoclonus–renal failuresyndrome. Abnormal levels of LIMP-2 have also been found in patients withhypertrophic cardiomyopathy.

Structure

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Human LIMP-2 has a theoretical molecular weight of 54.3 kDa and is 478amino acidsin length.[6]

Though LIMP-2 was initially discovered in 1985 by Lewis et al. from rat liverlysosomes,[7]LIMP-2 was cloned in 1992 by two groups, one isolated LIMP-2 from humanmetastaticpancreaticislettumor cells, and one from ratliverlysosomalmembranes.[8][9]LIMP-2 was isolated as a protein of approximate molecular weight 85 kDa, synthesized from a precursor oform of approximately 77 kDa. The weight discrepancy between its theoretical (54.3 kDa) and observed (85 kDa) is due to the presence of 10 highmannose-type N-linkedoligosaccharidechains in the human form of this protein, compared to 11 in mouse and rat.[10]LIMP-2 has two hydrophobic regions, one near theN-terminusand one near theC-terminus,as well as a shortisoleucine/leucine-richcytoplasmictail consisting of 20amino acidsthat serves as thelysosomaltargeting sequence.[11][12]LIMP-2 has been shown to be expressed inbrain,heart,liver,lungandkidney.[10]

Function

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The protein encoded by this gene is a type III glycoprotein that is located primarily in limiting membranes of lysosomes and endosomes. Studies of the similar proteins in mice and rat suggested that this protein may participate in membrane transportation and the reorganization of endosomal/lysosomal compartment.[13]In rat hepatic cells, LIMP-2 exhibited ahalf-lifefor internalization andlysosomaltransport of 32 min and 2.0 h, respectively, which resembled those of well-knownlysosomalproteins,lamp-1andlamp-2,though they have differentamino acidsequences in theircytoplasmictails.[14]

LIMP2 has recently been identified as a novel component ofintercalated discsincardiac muscle.Intercalated discsare composed ofgap junctions,adherens junctionsanddesmosomes,and are critical for the mechanical and electrical coupling of adjacentcardiomyocytes.The discovery of LIMP-2 as a component of this complex came about from a genetic screen of a homozygous,hypertensivetransgenicrat model ofreninoverexpression, in which a population of these rats rapidly developheart failureand another remains compensated.[15]Out of 143 differentially-regulated genes, LIMP-2 was identified to be significantly upregulated inheart failure-prone ratcardiac musclebiopsies, which also proved true in humanheart failure.Further analysis employing a LIMP-2 knockout mouse demonstrated that animals lacking LIMP-2 failed to flight a normalhypertrophicresponse followingangiotensin IItreatment, however they developed interstitialfibrosisanddilated cardiomyopathycoordinate with disruptedintercalated discstructure. Biochemical andimmunohistochemicalanalyses discovered that LIMP-2interactswithN-cadherinatintercalated discs,a function outside oflysosomalmembranes. Knockdown of LIMP-2 withRNA interferencedecreased the binding ofN-cadherinto thephosphorylatedform ofbeta-catenin,and LIMP-2 overexpression had the reverse effect.[16]

LIMP-2 plays other roles in other organs. Characteristic tubularproteinuriaobserved in LIMP-2 knockout mice has been shown to be due to a failure of inlysosomal/endosomalfusion, thus proteins reabsorbed in the proximal tubule of the kidney are not properly proteolyzed, causing theproteinuria.[17]Deficiency of LIMP-2 in mice was also reported to impair cell membrane transport processes and cause pelvic junction obstruction, deafness, and peripheral neuropathy.[18]

Clinical significance

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In patients withhypertrophic cardiomyopathydue toaortic stenosis,SCARB2mRNA is significantly upregulated, suggesting that LIMP-2 may act as ahypertrophicmarker.[16]

Mutations inSCARB2have been shown to cause action myoclonus–renal failuresyndrome, a rare syndrome characterized by progressive neurological disease and associated withproteinuria,kidney failure,andfocal segmental glomerulosclerosis.[19][20][21]

Mutations inSCARB2have also been shown to causeGaucher diseaseandmyoclonic epilepsy,[22]as LIMP-2 is critical for the proper sorting and targeting ofglucocerebrosidaseenzyme (the enzyme deficient inGaucher disease) tolysosomes.

SCARB2 is a receptor for two viruses that causehand, foot, and mouth diseasein children,Enterovirus 71andCoxsackievirus A16.[23]

Interactions

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LIMP-2 has been shown tointeractwith:

References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000138760Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000029426Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^"Entrez Gene: SCARB2 scavenger receptor class B, member 2".
  6. ^"Protein sequence of human SCARB2 (Uniprot ID: Q14108)".Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).Archived fromthe originalon 14 July 2015.Retrieved14 July2015.
  7. ^Lewis V, Green SA, Marsh M, Vihko P, Helenius A, Mellman I (Jun 1985)."Glycoproteins of the lysosomal membrane".The Journal of Cell Biology.100(6): 1839–47.doi:10.1083/jcb.100.6.1839.PMC2113609.PMID3922993.
  8. ^Fujita H, Takata Y, Kono A, Tanaka Y, Takahashi T, Himeno M, Kato K (Apr 1992). "Isolation and sequencing of a cDNA clone encoding the 85 kDa human lysosomal sialoglycoprotein (hLGP85) in human metastatic pancreas islet tumor cells".Biochemical and Biophysical Research Communications.184(2): 604–11.doi:10.1016/0006-291X(92)90632-U.PMID1374238.
  9. ^Akasaki K, Kinoshita H, Fukuzawa M, Maeda M, Yamaguchi Y, Furuno K, Tsuji H (Jan 1992)."Isolation and characterization of a novel membrane glycoprotein of 85,000 molecular weight from rat liver lysosomes".Chemical & Pharmaceutical Bulletin.40(1): 170–3.doi:10.1248/cpb.40.170.PMID1576668.
  10. ^abTabuchi N, Akasaki K, Sasaki T, Kanda N, Tsuji H (Oct 1997). "Identification and characterization of a major lysosomal membrane glycoprotein, LGP85/LIMP II in mouse liver".Journal of Biochemistry.122(4): 756–63.doi:10.1093/oxfordjournals.jbchem.a021820.PMID9399579.
  11. ^Ogata S, Fukuda M (Feb 1994)."Lysosomal targeting of Limp II membrane glycoprotein requires a novel Leu-Ile motif at a particular position in its cytoplasmic tail".The Journal of Biological Chemistry.269(7): 5210–7.doi:10.1016/S0021-9258(17)37676-7.PMID8106503.
  12. ^Sandoval IV, Arredondo JJ, Alcalde J, Gonzalez Noriega A, Vandekerckhove J, Jimenez MA, Rico M (Mar 1994)."The residues Leu(Ile)475-Ile(Leu, Val, Ala)476, contained in the extended carboxyl cytoplasmic tail, are critical for targeting of the resident lysosomal membrane protein LIMP II to lysosomes".The Journal of Biological Chemistry.269(9): 6622–31.doi:10.1016/S0021-9258(17)37418-5.PMID7509809.
  13. ^Gonzalez A, Valeiras M, Sidransky E, Tayebi N (Feb 2014)."Lysosomal integral membrane protein-2: a new player in lysosome-related pathology".Molecular Genetics and Metabolism.111(2): 84–91.doi:10.1016/j.ymgme.2013.12.005.PMC3924958.PMID24389070.
  14. ^Akasaki K, Michihara A, Fukuzawa M, Kinoshita H, Tsuji H (Sep 1994). "Cycling of an 85-kDa lysosomal membrane glycoprotein between the cell surface and lysosomes in cultured rat hepatocytes".Journal of Biochemistry.116(3): 670–6.PMID7852289.
  15. ^Schroen B, Heymans S, Sharma U, Blankesteijn WM, Pokharel S, Cleutjens JP, Porter JG, Evelo CT, Duisters R, van Leeuwen RE, Janssen BJ, Debets JJ, Smits JF, Daemen MJ, Crijns HJ, Bornstein P, Pinto YM (Sep 2004)."Thrombospondin-2 is essential for myocardial matrix integrity: increased expression identifies failure-prone cardiac hypertrophy".Circulation Research.95(5): 515–22.doi:10.1161/01.RES.0000141019.20332.3e.PMID15284191.
  16. ^abcSchroen B, Leenders JJ, van Erk A, Bertrand AT, van Loon M, van Leeuwen RE, Kubben N, Duisters RF, Schellings MW, Janssen BJ, Debets JJ, Schwake M, Høydal MA, Heymans S, Saftig P, Pinto YM (May 2007)."Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy".The Journal of Experimental Medicine.204(5): 1227–35.doi:10.1084/jem.20070145.PMC2118572.PMID17485520.
  17. ^Desmond MJ, Lee D, Fraser SA, Katerelos M, Gleich K, Martinello P, Li YQ, Thomas MC, Michelucci R, Cole AJ, Saftig P, Schwake M, Stapleton D, Berkovic SF, Power DA (Jun 2011). "Tubular proteinuria in mice and humans lacking the intrinsic lysosomal protein SCARB2/Limp-2".American Journal of Physiology. Renal Physiology.300(6): F1437–47.doi:10.1152/ajprenal.00015.2011.PMID21429972.S2CID25993341.
  18. ^Gamp AC, Tanaka Y, Lüllmann-Rauch R, Wittke D, D'Hooge R, De Deyn PP, Moser T, Maier H, Hartmann D, Reiss K, Illert AL, von Figura K, Saftig P (Mar 2003)."LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice".Human Molecular Genetics.12(6): 631–46.doi:10.1093/hmg/ddg062.PMID12620969.
  19. ^Balreira A, Gaspar P, Caiola D, Chaves J, Beirão I, Lima JL, Azevedo JE, Miranda MC (Jul 2008)."A nonsense mutation in the LIMP-2 gene associated with progressive myoclonic epilepsy and nephrotic syndrome".Human Molecular Genetics.17(14): 2238–43.doi:10.1093/hmg/ddn124.hdl:10400.16/885.PMID18424452.
  20. ^Berkovic SF, Dibbens LM, Oshlack A, Silver JD, Katerelos M, Vears DF, Lüllmann-Rauch R, Blanz J, Zhang KW, Stankovich J, Kalnins RM, Dowling JP, Andermann E, Andermann F, Faldini E, D'Hooge R, Vadlamudi L, Macdonell RA, Hodgson BL, Bayly MA, Savige J, Mulley JC, Smyth GK, Power DA, Saftig P, Bahlo M (Mar 2008)."Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis".American Journal of Human Genetics.82(3): 673–84.doi:10.1016/j.ajhg.2007.12.019.PMC2427287.PMID18308289.
  21. ^Hopfner F, Schormair B, Knauf F, Berthele A, Tölle TR, Baron R, Maier C, Treede RD, Binder A, Sommer C, Maihöfner C, Kunz W, Zimprich F, Heemann U, Pfeufer A, Näbauer M, Kääb S, Nowak B, Gieger C, Lichtner P, Trenkwalder C, Oexle K, Winkelmann J (27 October 2011)."Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features".BMC Neurology.11:134.doi:10.1186/1471-2377-11-134.PMC3222607.PMID22032306.
  22. ^Velayati A, DePaolo J, Gupta N, Choi JH, Moaven N, Westbroek W, Goker-Alpan O, Goldin E, Stubblefield BK, Kolodny E, Tayebi N, Sidransky E (Nov 2011)."A mutation in SCARB2 is a modifier in Gaucher disease".Human Mutation.32(11): 1232–8.doi:10.1002/humu.21566.PMC3196787.PMID21796727.
  23. ^Yamayoshi S, Yamashita Y, Li J, Hanagata N, Minowa T, Takemura T, Koike S (Jul 2009). "Scavenger receptor B2 is a cellular receptor for enterovirus 71".Nature Medicine.15(7): 798–801.doi:10.1038/nm.1992.PMID19543282.S2CID9192537.

Further reading

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