Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Reply to "The flip side of cardiolipin import"

Nature Medicine volume 17, pages 413–414 (2011)Cite this article

Subjects

Ray et al. reply:

The comments raised suggest that the CBD signature we identified within Atp8b1 is embedded in the cytoplasm and thus cannot access cardiolipin molecules imported from the external membrane leaflet. There are several other possibilities. First, the CBD may not be the only binding pocket, and another region(s) might initiate molecular interaction between Atp8b1 and cardiolipin on the cell surface. We have not excluded other high affinity sites as these domains would not have been detected if the motifs were masked because of misfolding of Atp8b1 mutants that were generated using our deletional mapping approach for binding assays. In this scenario, one could postulate the existence of two or more cooperatively interacting cardiolipin binding sites, perhaps regulated by ATP hydrolysis, as in the transport of lipids driven by ABC transporters5. In fact, biphasic binding of cardiolipin is characteristic of several proteins, such as mitochondrial creatine kinase and cytochrome c6,7. Second, our CBD may be an external loop, and not internal as predicted. Third, it is possible that the CBD region identified within the cytoplasmic loop is an authentic, solitary interaction site for cardiolipin. Our results resemble the molecular behavior of some receptor interactions in which residues within predicted cytosolic loops directly modulate binding of these surface receptors with their cognate extracellular ligands8,9,10. The CBD region we have identified might even be involved in bidirectional transport or show substantial flexibility and conformational range like those of other transporters to allow capture of its cargo11; however, this latter possibility awaits structural and accessibility measurements. Last, we do not implicate Atp8b1 as the only carrier for cardiolipin, nor exclude promiscuity of Atp8b1 for several substrates, as occurs for floppases12.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cardiolipin within mouse lung epithelia.
Figure 2: Cardiolipin import by Atp8b1 in mouse lung epithelia.

References

  1. Paulusma, C.C., Houwen, R.H.J. & Williamson, P.L. Nat. Med. 17, 413 (2011).

    Article  CAS  Google Scholar 

  2. Zhou, X. & Graham, T.R. Proc. Natl. Acad. Sci. USA 106, 16586–16591 (2009).

    Article  CAS  Google Scholar 

  3. Ray, N.B. et al. Nat. Med. 16, 1120–1127 (2010).

    Article  CAS  Google Scholar 

  4. Kagan, V.E. et al. Mol. Nutr. Food Res. 53, 104–114 (2009).

    Article  CAS  Google Scholar 

  5. Siarheyeva, A. & Sharom, F.J. Biochem. J. 419, 317–328 (2009).

    Article  CAS  Google Scholar 

  6. Schlattner, U. et al. Biochim. Biophys. Acta 1788, 2032–2047 (2009).

    Article  CAS  Google Scholar 

  7. Kagan, V.E. et al. Free Radic. Biol. Med. 37, 1963–1985 (2004).

    Article  CAS  Google Scholar 

  8. Lai, J. et al. J. Pharmacol. Exp. Ther. 262, 173–180 (1992).

    CAS  PubMed  Google Scholar 

  9. Chazenbalk, G.D., Nagayama, Y., Russo, D., Wadsworth, H.L. & Rapoport, B. J. Biol. Chem. 265, 20970–20975 (1990).

    CAS  PubMed  Google Scholar 

  10. Wada, K. et al. Protein Expr. Purif. 6, 228–236 (1995).

    Article  CAS  Google Scholar 

  11. Ward, A., Reyes, C.L., Yu, J., Roth, C.B. & Chang, G. Proc. Natl. Acad. Sci. USA 104, 19005–19010 (2007).

    Article  CAS  Google Scholar 

  12. Zhou, J., You, Y., Ryan, A.J. & Mallampalli, R.K. J. Lipid Res. 45, 1758–1767 (2004).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Bill B Chen & Rama K Mallampalli

  2. Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Jian Fei Jiang & Valerian E Kagan

  3. Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA

    Nancy B Ray

Authors
  1. Bill B Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jian Fei Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nancy B Ray
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Valerian E Kagan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rama K Mallampalli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rama K Mallampalli.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, B., Jiang, J., Ray, N. et al. Reply to "The flip side of cardiolipin import". Nat Med 17, 413–414 (2011). https://doi.org/10.1038/nm0411-413b

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0411-413b

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing