Advertisement

Journal of Bioenergetics and Biomembranes

, Volume 39, Issue 5–6, pp 447–452 | Cite as

Cholesterol fill-in model: mechanism for substrate recognition by ABC proteins

  • Yasuhisa Kimura
  • Atsushi Kodan
  • Michinori Matsuo
  • Kazumitsu Ueda
Transport ATPases: Structure, Mechanism and Relevance to Multiple Diseases

Abstract

Many of the 48 or 49 human ABC proteins are involved in lipid homeostasis and in defence against hydrophobic substances in food and the environment. Defects in their functions cause various diseases, suggesting that they play very important roles in human health; however, the mechanism of how they handle enormous numbers of hydrophobic compounds with various structures and molecular weights, or phospholipids and cholesterol, major components of cellular membranes, is not known. We compared the functions of drug-transporting and lipid-transporting ABC proteins, and found that (1) ABC proteins, either lipid or drug transporters, have a similar substrate binding site which recognizes PL and cholesterol, or drugs and cholesterol; (2) Cholesterol in membranes binds to various ABC proteins together with PL or drugs, and plays an important role in substrate recognition, especially by ABCB1/MDR1, where cholesterol fills the empty space in the substrate binding site when small drugs bind to it. ABC proteins exert very flexible substrate recognition, i.e., one-to-many interaction rather than the conventional rigid one-to-one interaction. We propose calling the mechanism the “cholesterol fill-in model”.

Keywords

ABC proteins Lipid transporter Drug transporter Cholesterol MDR1 ABCA1 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bodzioch M, Orso E, Klucken J, Langmann T, Bottcher A, Diederich W, Drobnik W, Barlage S, Buchler C, Porsch-Ozcurumez M, Kaminski W, Hahmann H, Oette K, Rothe G, Aslanidis C, Lackner K, Schmitz G (1999) Nat Genet 22:347–351CrossRefGoogle Scholar
  2. Brooks-Wilson A, Marcil M, Clee S, Zhang L, Roomp K, van Dam M, Yu L, Brewer C, Collins J, Molhuizen H, Loubser O, Ouelette B, Fichter K, Ashbourne-Excoffon K, Sensen C, Scherer S, Mott S, Denis M, Martindale D, Frohlich J, Morgan K, Koop B, Pimstone S, Kastelein J, Hayden M (1999) Nat Genet 22:336–345CrossRefGoogle Scholar
  3. Fielding PE, Nagao K, Hakamata H, Chimini G, Fielding CJ (2000) Biochemistry 39:14113–14120CrossRefGoogle Scholar
  4. Fitzgerald ML, Morris AL, Rhee JS, Andersson LP, Mendez AJ, Freeman MW (2002) J Biol Chem 277:33178–33187CrossRefGoogle Scholar
  5. Hanada K, Kumagai K, Yasuda S, Miura Y, Kawano M, Fukasawa M, Nishijima M (2003) Nature 426:803–809CrossRefGoogle Scholar
  6. Hayashi M, Abe-Dohmae S, Okazaki M, Ueda K, Yokoyama S (2005) J Lipid Res 46:1703–1711CrossRefGoogle Scholar
  7. Kimura Y, Kioka N, Kato H, Matsuo M, Ueda K (2007) Biochem J 401:597–605CrossRefGoogle Scholar
  8. Kino K, Taguchi Y, Yamada K, Komano T, Ueda K (1996) FEBS Lett 399:29–32CrossRefGoogle Scholar
  9. Kobayashi A, Takanezawa Y, Hirata T, Shimizu Y, Misasa K, Kioka N, Arai H, Ueda K, Matsuo M (2006) J Lipid Res 47:1791–1802CrossRefGoogle Scholar
  10. Koseki M, Hirano KI, Masuda D, Ikegami C, Tanaka M, Ota A, Sandoval JC, Nakagawa-Toyama Y, Sato SB, Kobayashi T, Shimada Y, Ohno-Iwashita Y, Matsuura F, Shimomura I, Yamashita S (2007) J Lipid Res 48:299–306CrossRefGoogle Scholar
  11. Landry YD, Denis M, Nandi S, Bell S, Vaughan AM, Zha X (2006) J Biol Chem 281:36091–36101CrossRefGoogle Scholar
  12. Loo TW, Bartlett MC, Clarke DM (2006) Biochem J 22:22Google Scholar
  13. Morita SY, Kobayashi A, Takanezawa Y, Kioka N, Handa T, Arai H, Matsuo M, Ueda K (2007) Hepatology 46:188–199CrossRefGoogle Scholar
  14. Nagao K, Takahashi K, Hanada K, Kioka N, Matsuo M, Ueda K (2007) J Biol Chem 282:14868–14874CrossRefGoogle Scholar
  15. Ruetz S, Gros P (1994) Cell 77:1071–1081CrossRefGoogle Scholar
  16. Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette J, Deleuze J, Brewer H, Duverger N, Denefle P, Assmann G (1999) Nat Genet 22:352–355CrossRefGoogle Scholar
  17. Sano O, Kobayashi A, Nagao K, Kumagai K, Kioka N, Hanada K, Ueda K, Matsuo M (2007) J Lipid Res 48:2377–2384CrossRefGoogle Scholar
  18. Smith AJ, van Helvoort A, van Meer G, Szabo K, Welker E, Szakacs G, Varadi A, Sarkadi B, Borst P (2000) J Biol Chem 275:23530–23539CrossRefGoogle Scholar
  19. Taguchi Y, Kino K, Morishima M, Komano T, Kane SE, Ueda K (1997a) Biochemistry 36:8883–8889CrossRefGoogle Scholar
  20. Taguchi Y, Morishima M, Komano T, Ueda K (1997b) FEBS Lett 413:142–146CrossRefGoogle Scholar
  21. Takahashi K, Kimura Y, Kioka N, Matsuo M, Ueda K (2006) J Biol Chem 281:10760–10768CrossRefGoogle Scholar
  22. Tanaka AR, Ikeda Y, Abe-Dohmae S, Arakawa R, Sadanami K, Kidera A, Nakagawa S, Nagase T, Aoki R, Kioka N, Amachi T, Yokoyama S, Ueda K (2001) Biochem Biophys Res Commun 283:1019–1025CrossRefGoogle Scholar
  23. Tanaka AR, Abe-Dohmae S, Ohnishi T, Aoki R, Morinaga G, Okuhira KI, Ikeda Y, Kano F, Matsuo M, Kioka N, Amachi T, Murata M, Yokoyama S, Ueda K (2003) J Biol Chem 278:8815–8819CrossRefGoogle Scholar
  24. Ueda K, Cardarelli C, Gottesman MM, Pastan I (1987) Proc Natl Acad Sci U S A 84:3004–3008CrossRefGoogle Scholar
  25. van der Bliek AM, Kooiman PM, Schneider C, Borst P (1988) Gene 71:401–411CrossRefGoogle Scholar
  26. Wang N, Silver D, Costet P, Tall A (2000) J Biol Chem 275:33053–33058CrossRefGoogle Scholar
  27. Wang N, Silver DL, Thiele C, Tall AR (2001) J Biol Chem 276:23742–23747CrossRefGoogle Scholar
  28. Wang N, Lan D, Gerbod-Giannone M, Linsel-Nitschke P, Jehle AW, Chen W, Martinez LO, Tall AR (2003) J Biol Chem 278:42906–42912CrossRefGoogle Scholar
  29. Wang J, Sun F, Zhang DW, Ma Y, Xu F, Belani JD, Cohen JC, Hobbs HH, Xie XS (2006) J Biol Chem 281:27894–27904CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Yasuhisa Kimura
    • 2
  • Atsushi Kodan
    • 2
  • Michinori Matsuo
    • 2
  • Kazumitsu Ueda
    • 1
  1. 1.Institute for Integrated Cell-Material Sciences and Laboratory of Cellular Biochemistry,Division of Applied Life SciencesGraduate School of Agriculture, Kyoto UniversityKyotoJapan
  2. 2.Laboratory of Cellular Biochemistry, Division of Applied Life SciencesGraduate School of Agriculture, Kyoto UniversityKyotoJapan

Personalised recommendations