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ATP-binding cassette, sub-family A (ABC1), member 1
Identifiers
Symbols ABCA1; ABC-1; ABC1; CERP; FLJ14958; HDLDT1; TGD
External IDs OMIM600046 MGI99607 HomoloGene21130 GeneCards: ABCA1 Gene
RNA expression pattern
PBB GE ABCA1 203504 s at tn.png
PBB GE ABCA1 216066 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 19 11303
Ensembl ENSG00000165029 ENSMUSG00000015243
UniProt O95477 Q8BPY1
RefSeq (mRNA) NM_005502 NM_013454
RefSeq (protein) NP_005493 NP_038482
Location (UCSC) Chr 9:
106.58 - 106.73 Mb
Chr 4:
53.05 - 53.18 Mb
PubMed search [1] [2]

ATP-binding cassette transporter ABCA1 (member 1 of human transporter sub-family ABCA), also known as the cholesterol efflux regulatory protein (CERP) is a protein which in humans is encoded by the ABCA1 gene.[1] This transporter is a major regulator of cellular cholesterol and phospholipid homeostasis.

Contents

Discovery of mutations in ABCA1 as the cause of Tangier's Disease

ABCA1 was discovered as the mutation causing Tangier's Disease by several groups in 1998. Gerd Schmitz's group in Germany[2] and Michael Hayden's group in British Columbia[3] were using standard genetics techniques and DNA from family pedigrees to locate the mutation. Richard Lawn's group at CV Therapeutics in Palo Alto, CA used cDNA microarrays, which were relatively new at the time, to assess gene expression profiles from cell lines created from normal and effected individuals.[4] They showed cell lines from patients with Tangier's disease showed differential regulation of the ABCA1 gene. Subsequent sequencing of the gene identified the mutations. This group received an award from the American Heart Association for their discovery.[5 ]

Function

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABCA, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABCA subfamily. Members of the ABCA subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. With cholesterol as its substrate, this protein functions as a cholesterol efflux pump in the cellular lipid removal pathway.[6][7]

Physiological role

ABCA1 mediates the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins (apo-A1 and apoE), which then form nascent high-density lipoproteins (HDL). It also mediates the transport of lipids between Golgi and cell membrane. Since this protein is needed throughout the body it is expressed ubiquitously as a 220-kDa protein. It is present in higher quantities in tissues that shuttle or are involved in the turnover of lipids such as the liver, the small intestine and adipose tissue.[8]

Factors that act upon the ABCA1 transporter's expression or its posttranslational modification are also molecules that are involved in its subsequent function like fatty acids, cholesterol and also cytokines and cyclic adenosine monophosphate.[9]

Clinical significance

Mutations in this gene have been associated with Tangier disease and familial high-density lipoprotein deficiency. ABCA1 has been shown to be reduced in Tangier disease which features physiological deficiencies of HDL.[10][11]

See also

Interactions

ABCA1 has been shown to interact with Apolipoprotein A1,[12] FADD,[13] XPC[14] and SNTB2.[15]

References

  1. ^ Luciani MF, Denizot F, Savary S, Mattei MG, Chimini G (May 1994). "Cloning of two novel ABC transporters mapping on human chromosome 9". Genomics 21 (1): 150–9. doi:10.1006/geno.1994.1237. PMID 8088782.  
  2. ^ Bodzioch M, Orsó E, Klucken J, Langmann T, Böttcher A, Diederich W, Drobnik W, Barlage S, Büchler C, Porsch-Ozcürümez M, Kaminski WE, Hahmann HW, Oette K, Rothe G, Aslanidis C, Lackner KJ, Schmitz G (August 1999). "The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease". Nature Genetics 22 (4): 347–51. doi:10.1038/11914. PMID 10431237.  
  3. ^ Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, Yu L, Brewer C, Collins JA, Molhuizen HO, Loubser O, Ouelette BF, Fichter K, Ashbourne-Excoffon KJ, Sensen CW, Scherer S, Mott S, Denis M, Martindale D, Frohlich J, Morgan K, Koop B, Pimstone S, Kastelein JJ, Genest J, Hayden MR (August 1999). "Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency". Nature Genetics 22 (4): 336–45. doi:10.1038/11905. PMID 10431236.  
  4. ^ Lawn RM, Wade DP, Garvin MR, Wang X, Schwartz K, Porter JG, Seilhamer JJ, Vaughan AM, Oram JF (October 1999). "The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway". The Journal of Clinical Investigation 104 (8): R25–31. doi:10.1172/JCI8119. PMID 10525055.  
  5. ^ "American Heart Association Selects CV Therapeutics' Discovery of Role Of 'Good' Cholesterol-Regulating Gene as Top Ten 1999 Research Advances In Heart Disease". PR Newswire Association. 2000-01-03. http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/01-03-2000/0001106348&EDATE=. Retrieved 2009-05-08.  
  6. ^ "Entrez Gene: ABCA1 ATP-binding cassette, sub-family A (ABC1), member 1". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=19.  
  7. ^ Schmitz G, Langmann T (April 2001). "Structure, function and regulation of the ABC1 gene product". Curr. Opin. Lipidol. 12 (2): 129–40. doi:10.1097/00041433-200104000-00006. PMID 11264984.  
  8. ^ E. M. Wagner, F. Basso, C. S. Kim, M. J. A. Amar, "ABC lipid transporters", in AccessScience@McGraw-Hill
  9. ^ Yokoyama S (February 2006). "ABCA1 and biogenesis of HDL". J. Atheroscler. Thromb. 13 (1): 1–15. PMID 16505586. http://www.jstage.jst.go.jp/article/jat/13/1/13_1/_article.  
  10. ^ Ordovas JM (March 2000). "ABC1: the gene for Tangier disease and beyond". Nutr. Rev. 58 (3 Pt 1): 76–9. PMID 10812922.  
  11. ^ Oram JF, Vaughan AM (June 2000). "ABCA1-mediated transport of cellular cholesterol and phospholipids to HDL apolipoproteins". Curr. Opin. Lipidol. 11 (3): 253–60. doi:10.1097/00041433-200006000-00005. PMID 10882340.  
  12. ^ Fitzgerald, Michael L; Morris Andrea L, Rhee Jeongmi S, Andersson Lorna P, Mendez Armando J, Freeman Mason W (Sep. 2002). "Naturally occurring mutations in the largest extracellular loops of ABCA1 can disrupt its direct interaction with apolipoprotein A-I". J. Biol. Chem. (United States) 277 (36): 33178–87. doi:10.1074/jbc.M204996200. ISSN 0021-9258. PMID 12084722.  
  13. ^ Buechler, Christa; Bared Salim Maa, Aslanidis Charalampos, Ritter Mirko, Drobnik Wolfgang, Schmitz Gerd (Nov. 2002). "Molecular and functional interaction of the ATP-binding cassette transporter A1 with Fas-associated death domain protein". J. Biol. Chem. (United States) 277 (44): 41307–10. doi:10.1074/jbc.C200436200. ISSN 0021-9258. PMID 12235128.  
  14. ^ Shimizu, Yuichiro; Iwai Shigenori, Hanaoka Fumio, Sugasawa Kaoru (Jan. 2003). "Xeroderma pigmentosum group C protein interacts physically and functionally with thymine DNA glycosylase". EMBO J. (England) 22 (1): 164–73. doi:10.1093/emboj/cdg016. ISSN 0261-4189. PMID 12505994.  
  15. ^ Buechler, Christa; Boettcher Alfred, Bared Salim Maa, Probst Mario C O, Schmitz Gerd (May. 2002). "The carboxyterminus of the ATP-binding cassette transporter A1 interacts with a beta2-syntrophin/utrophin complex". Biochem. Biophys. Res. Commun. (United States) 293 (2): 759–65. doi:10.1016/S0006-291X(02)00303-0. ISSN 0006-291X. PMID 12054535.  

Further reading

  • Tam SP, Mok L, Chimini G, Vasa M, Deeley RG (2006). "ABCA1 mediates high-affinity uptake of 25-hydroxycholesterol by membrane vesicles and rapid efflux of oxysterol by intact cells.". Am J Physiol Cell Physiol. 291 (3): C490–502. doi:10.1152/ajpcell.00055.2006. PMID 16611739.  
  • Oram JF (2003). "ATP-binding cassette transporter A1 and cholesterol trafficking.". Curr. Opin. Lipidol. 13 (4): 373–81. doi:10.1097/00041433-200208000-00004. PMID 12151852.  
  • Hong SH, Rhyne J, Zeller K, Miller M (2003). "ABCA1(Alabama): a novel variant associated with HDL deficiency and premature coronary artery disease.". Atherosclerosis 164 (2): 245–50. doi:10.1016/S0021-9150(02)00106-5. PMID 12204794.  
  • Kozak M (2003). "Emerging links between initiation of translation and human diseases.". Mamm. Genome 13 (8): 401–10. doi:10.1007/s00335-002-4002-5. PMID 12226704.  
  • Joyce C, Freeman L, Brewer HB, Santamarina-Fojo S (2004). "Study of ABCA1 function in transgenic mice.". Arterioscler. Thromb. Vasc. Biol. 23 (6): 965–71. doi:10.1161/01.ATV.0000055194.85073.FF. PMID 12615681.  
  • Singaraja RR, Brunham LR, Visscher H, et al. (2004). "Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene.". Arterioscler. Thromb. Vasc. Biol. 23 (8): 1322–32. doi:10.1161/01.ATV.0000078520.89539.77. PMID 12763760.  
  • Nofer JR, Remaley AT (2005). "Tangier disease: still more questions than answers.". Cell. Mol. Life Sci. 62 (19-20): 2150–60. doi:10.1007/s00018-005-5125-0. PMID 16235041.  
  • Yokoyama S (2006). "ABCA1 and biogenesis of HDL.". J. Atheroscler. Thromb. 13 (1): 1–15. PMID 16505586.  
  • Schmitz G, Schambeck CM (2006). "Molecular defects in the ABCA1 pathway affect platelet function.". Pathophysiol. Haemost. Thromb. 35 (1-2): 166–74. doi:10.1159/000093563. PMID 16855366.  
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