Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
International Journal of Molecular Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1107-3756 Online ISSN: 1791-244X
Journal Cover
August-2016 Volume 38 Issue 2

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
August-2016 Volume 38 Issue 2

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Homooligomerization of ABCA3 and its functional significance

  • Authors:
    • Sabrina Frixel
    • Amelie S. Lotz-Havla
    • Sunčana Kern
    • Eva Kaltenborn
    • Thomas Wittmann
    • Søren W. Gersting
    • Ania C. Muntau
    • Ralf Zarbock
    • Matthias Griese
  • View Affiliations / Copyright

    Affiliations: German Centre for Lung Research, Dr von Hauner Children's Hospital, Ludwig-Maximilians University, D-80337 Munich, Germany, Department of Molecular Pediatrics, Dr von Hauner Children's Hospital, Ludwig-Maximilians University, D-80337 Munich, Germany, University Children's Hospital, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany
  • Pages: 558-566
    |
    Published online on: June 21, 2016
       https://doi.org/10.3892/ijmm.2016.2650
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

ABCA3 is a surfactant lipid transporter in the limiting membrane of lamellar bodies in alveolar type II cells. Mutations in the ATP-binding cassette, sub-family A (ABC1), member 3 (ABCA3) gene cause respiratory distress syndrome in newborns, and chronic interstitial lung disease in children and adults. ABCA3 belongs to the class of full ABC transporters, which are supposed to be functional in their monomeric forms. Although other family members e.g., ABCA1 and ABCC7 have been shown to function as oligomers, the oligomerization state of ABCA3 is unknown. In the present study, the oligomerization of ABCA3 was investigated in cell lysates and crude membrane preparations from transiently and stably transfected 293 cells using blue native PAGE (BN-PAGE), gel filtration and co-immunoprecipitation. Additionally, homooligomerization was examined in vivo in cells using bioluminescence resonance energy transfer (BRET). Using BN-PAGE and gel filtration, we demonstrate that non-denatured ABCA3 exists in different oligomeric forms, with monomers (45%) and tetramers (30%) being the most abundant forms. Furthermore, we also show the existence of 20% dimers and 5% trimers. BRET analyses verified intermolecular interactions in vivo. Our results also demonstrated that the arrest of ABCA3 in the endoplasmic reticulum (ER), either through drug treatment or induced by mutations in ABCA3, inhibited the propensity of the protein to form dimers. Based on our results, we suggest that transporter oligomerization is crucial for ABCA3 function and that a disruption of oligomerization due to mutations represents a novel pathomechanism in ABCA3-associated lung disease.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

View References

1 

Wilkens S: Structure and mechanism of ABC transporters. F1000Prime Rep. 7:142015. View Article : Google Scholar : PubMed/NCBI

2 

Dean M, Hamon Y and Chimini G: The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res. 42:1007–1017. 2001.PubMed/NCBI

3 

Bodzioch M, Orsó E, Klucken J, Langmann T, Böttcher A, Diederich W, Drobnik W, Barlage S, Büchler C, Porsch-Ozcürümez M, et al: The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet. 22:347–351. 1999. View Article : Google Scholar : PubMed/NCBI

4 

Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, Yu L, Brewer C, Collins JA, Molhuizen HO, et al: Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet. 22:336–345. 1999. View Article : Google Scholar : PubMed/NCBI

5 

Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram, Gerrard B, Baird L, Stauffer D, Peiffer A, et al: A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 15:236–246. 1997. View Article : Google Scholar : PubMed/NCBI

6 

Bergen AA, Plomp AS, Schuurman EJ, Terry S, Breuning M, Dauwerse H, Swart J, Kool M, van Soest S, Baas F, et al: Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet. 25:228–231. 2000. View Article : Google Scholar : PubMed/NCBI

7 

Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL, et al: Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA. Science. 245:1066–1073. 1989. View Article : Google Scholar : PubMed/NCBI

8 

Kartner N, Riordan JR and Ling V: Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science. 221:1285–1288. 1983. View Article : Google Scholar : PubMed/NCBI

9 

Cole SP: Multidrug resistance protein 1 (MRP1, ABCC1), a 'multitasking' ATP-binding cassette (ABC) transporter. J Biol Chem. 289:30880–30888. 2014. View Article : Google Scholar : PubMed/NCBI

10 

Mo W and Zhang JT: Oligomerization of human ATP-binding cassette transporters and its potential significance in human disease. Expert Opin Drug Metab Toxicol. 5:1049–1063. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Jetté L, Potier M and Béliveau R: P-glycoprotein is a dimer in the kidney and brain capillary membranes: Effect of cyclosporin A and SDZ-PSC 833. Biochemistry. 36:13929–13937. 1997. View Article : Google Scholar : PubMed/NCBI

12 

Soszyński M, Kałuzna A, Rychlik B, Sokal A and Bartosz G: Radiation inactivation suggests that human multidrug resistance-associated protein 1 occurs as a dimer in the human erythrocyte membrane. Arch Biochem Biophys. 354:311–316. 1998. View Article : Google Scholar

13 

Ramjeesingh M, Kidd JF, Huan LJ, Wang Y and Bear CE: Dimeric cystic fibrosis transmembrane conductance regulator exists in the plasma membrane. Biochem J. 374:793–797. 2003. View Article : Google Scholar : PubMed/NCBI

14 

Albrecht C and Viturro E: The ABCA subfamily - gene and protein structures, functions and associated hereditary diseases. Pflugers Arch. 453:581–589. 2007. View Article : Google Scholar

15 

Denis M, Haidar B, Marcil M, Bouvier M, Krimbou L and Genest J: Characterization of oligomeric human ATP binding cassette transporter A1. Potential implications for determining the structure of nascent high density lipoprotein particles. J Biol Chem. 279:41529–41536. 2004. View Article : Google Scholar : PubMed/NCBI

16 

Ban N, Matsumura Y, Sakai H, Takanezawa Y, Sasaki M, Arai H and Inagaki N: ABCA3 as a lipid transporter in pulmonary surfactant biogenesis. J Biol Chem. 282:9628–9634. 2007. View Article : Google Scholar : PubMed/NCBI

17 

Matsumura Y, Sakai H, Sasaki M, Ban N and Inagaki N: ABCA3-mediated choline-phospholipids uptake into intracellular vesicles in A549 cells. FEBS Lett. 581:3139–3144. 2007. View Article : Google Scholar : PubMed/NCBI

18 

Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA and Dean M: ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med. 350:1296–1303. 2004. View Article : Google Scholar : PubMed/NCBI

19 

Bullard JE, Wert SE, Whitsett JA, Dean M and Nogee LM: ABCA3 mutations associated with pediatric interstitial lung disease. Am J Respir Crit Care Med. 172:1026–1031. 2005. View Article : Google Scholar : PubMed/NCBI

20 

Campo I, Zorzetto M, Mariani F, Kadija Z, Morbini P, Dore R, Kaltenborn E, Frixel S, Zarbock R, Liebisch G, et al: A large kindred of pulmonary fibrosis associated with a novel ABCA3 gene variant. Respir Res. 15:432014. View Article : Google Scholar : PubMed/NCBI

21 

Weichert N, Kaltenborn E, Hector A, Woischnik M, Schams A, Holzinger A, Kern S and Griese M: Some ABCA3 mutations elevate ER stress and initiate apoptosis of lung epithelial cells. Respir Res. 12:42011. View Article : Google Scholar : PubMed/NCBI

22 

Engelbrecht S, Kaltenborn E, Griese M and Kern S: The surfactant lipid transporter ABCA3 is N-terminally cleaved inside LAMP3-positive vesicles. FEBS Lett. 584:4306–4312. 2010. View Article : Google Scholar : PubMed/NCBI

23 

Gersting SW, Lotz-Havla AS and Muntau AC: Bioluminescence resonance energy transfer: An emerging tool for the detection of protein-protein interaction in living cells. Methods Mol Biol. 815:253–263. 2012. View Article : Google Scholar

24 

Matsumura Y, Ban N, Ueda K and Inagaki N: Characterization and classification of ATP-binding cassette transporter ABCA3 mutants in fatal surfactant deficiency. J Biol Chem. 281:34503–34514. 2006. View Article : Google Scholar : PubMed/NCBI

25 

Bischof JC and He X: Thermal stability of proteins. Ann NY Acad Sci. 1066:12–33. 2005. View Article : Google Scholar

26 

Hamdan FF, Percherancier Y, Breton B and Bouvier M: Monitoring protein-protein interactions in living cells by biolu-minescence resonance energy transfer (BRET). Curr Protoc Neurosci. Chapter 5, Unit 5.23. 2006. View Article : Google Scholar

27 

Nylander S and Kalies I: Brefeldin A, but not monensin, completely blocks CD69 expression on mouse lymphocytes: Efficacy of inhibitors of protein secretion in protocols for intracellular cytokine staining by flow cytometry. J Immunol Methods. 224:69–76. 1999. View Article : Google Scholar : PubMed/NCBI

28 

Trompier D, Alibert M, Davanture S, Hamon Y, Pierres M and Chimini G: Transition from dimers to higher oligomeric forms occurs during the ATPase cycle of the ABCA1 transporter. J Biol Chem. 281:20283–20290. 2006. View Article : Google Scholar : PubMed/NCBI

29 

Heuberger EH, Veenhoff LM, Duurkens RH, Friesen RH and Poolman B: Oligomeric state of membrane transport proteins analyzed with blue native electrophoresis and analytical ultra-centrifugation. J Mol Biol. 317:591–600. 2002. View Article : Google Scholar : PubMed/NCBI

30 

Matsumoto N, Tamura S, Furuki S, Miyata N, Moser A, Shimozawa N, Moser HW, Suzuki Y, Kondo N and Fujiki Y: Mutations in novel peroxin gene PEX26 that cause peroxisome-biogenesis disorders of complementation group 8 provide a genotype-phenotype correlation. Am J Hum Genet. 73:233–246. 2003. View Article : Google Scholar : PubMed/NCBI

31 

Fitzgerald ML, Okuhira K, Short GF III, Manning JJ, Bell SA and Freeman MW: ATP-binding cassette transporter A1 contains a novel C-terminal VFVNFA motif that is required for its cholesterol efflux and ApoA-I binding activities. J Biol Chem. 279:48477–48485. 2004. View Article : Google Scholar : PubMed/NCBI

32 

Wang S, Yue H, Derin RB, Guggino WB and Li M: Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity. Cell. 103:169–179. 2000. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Frixel S, Lotz-Havla AS, Kern S, Kaltenborn E, Wittmann T, Gersting SW, Muntau AC, Zarbock R and Griese M: Homooligomerization of ABCA3 and its functional significance. Int J Mol Med 38: 558-566, 2016.
APA
Frixel, S., Lotz-Havla, A.S., Kern, S., Kaltenborn, E., Wittmann, T., Gersting, S.W. ... Griese, M. (2016). Homooligomerization of ABCA3 and its functional significance. International Journal of Molecular Medicine, 38, 558-566. https://doi.org/10.3892/ijmm.2016.2650
MLA
Frixel, S., Lotz-Havla, A. S., Kern, S., Kaltenborn, E., Wittmann, T., Gersting, S. W., Muntau, A. C., Zarbock, R., Griese, M."Homooligomerization of ABCA3 and its functional significance". International Journal of Molecular Medicine 38.2 (2016): 558-566.
Chicago
Frixel, S., Lotz-Havla, A. S., Kern, S., Kaltenborn, E., Wittmann, T., Gersting, S. W., Muntau, A. C., Zarbock, R., Griese, M."Homooligomerization of ABCA3 and its functional significance". International Journal of Molecular Medicine 38, no. 2 (2016): 558-566. https://doi.org/10.3892/ijmm.2016.2650
Copy and paste a formatted citation
x
Spandidos Publications style
Frixel S, Lotz-Havla AS, Kern S, Kaltenborn E, Wittmann T, Gersting SW, Muntau AC, Zarbock R and Griese M: Homooligomerization of ABCA3 and its functional significance. Int J Mol Med 38: 558-566, 2016.
APA
Frixel, S., Lotz-Havla, A.S., Kern, S., Kaltenborn, E., Wittmann, T., Gersting, S.W. ... Griese, M. (2016). Homooligomerization of ABCA3 and its functional significance. International Journal of Molecular Medicine, 38, 558-566. https://doi.org/10.3892/ijmm.2016.2650
MLA
Frixel, S., Lotz-Havla, A. S., Kern, S., Kaltenborn, E., Wittmann, T., Gersting, S. W., Muntau, A. C., Zarbock, R., Griese, M."Homooligomerization of ABCA3 and its functional significance". International Journal of Molecular Medicine 38.2 (2016): 558-566.
Chicago
Frixel, S., Lotz-Havla, A. S., Kern, S., Kaltenborn, E., Wittmann, T., Gersting, S. W., Muntau, A. C., Zarbock, R., Griese, M."Homooligomerization of ABCA3 and its functional significance". International Journal of Molecular Medicine 38, no. 2 (2016): 558-566. https://doi.org/10.3892/ijmm.2016.2650
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team