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Author Notes:

Email Address: Kuai Yu:kyu3@emory.edu; H Criss Hartzell :criss.hartzell@emory.edu

KY, Conceived and designed experiments, Performed and analyzed all patch clamp experiments, Prepared figures, Wrote the manuscript.

JMW, Contributed to experimental design, Performed and analyzed scrambling experiments, Helped write the manuscript.

KL, Assisted with phospholipid scrambling experiments, Tissue culture, Helped to write and edit the manuscript.

EAO, Assisted with development and analysis of homology models.

YYC, Designed and made all the cDNA constructs, chimeras, and mutants, Maintained tissue culture, Performed transfections.

HCH, Conceived and designed experiments, Performed and analyzed scrambling experiments, Edited figures, Wrote the manuscript.

The funder had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

The authors declare that no competing interests exist.


Research Funding:

Supported by NIH grants GM60448-12 and EY114852-11 to HCH.

Jarred Whitlock was supported by an NIH Training Grant 5T32GM008367-25.

This research project was supported in part by the Emory University Integrated Cellular Imaging Microscopy Core.

Identification of a lipid scrambling domain in ANO6/TMEM16F.


Journal Title:



Volume 4


Type of Work:

Article | Final Publisher PDF


Phospholipid scrambling (PLS) is a ubiquitous cellular mechanism involving the regulated bidirectional transport of phospholipids down their concentration gradient between membrane leaflets. ANO6/TMEM16F has been shown to be essential for Ca(2+)-dependent PLS, but controversy surrounds whether ANO6 is a phospholipid scramblase or an ion channel like other ANO/TMEM16 family members. Combining patch clamp recording with measurement of PLS, we show that ANO6 elicits robust Ca(2+)-dependent PLS coinciding with ionic currents that are explained by ionic leak during phospholipid translocation. By analyzing ANO1-ANO6 chimeric proteins, we identify a domain in ANO6 necessary for PLS and sufficient to confer this function on ANO1, which normally does not scramble. Homology modeling shows that the scramblase domain forms an unusual hydrophilic cleft that faces the lipid bilayer and may function to facilitate translocation of phospholipid between membrane leaflets. These findings provide a mechanistic framework for understanding PLS and how ANO6 functions in this process.

Copyright information:

© 2015, Yu et al

This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits making multiple copies, distribution, public display, and publicly performance, distribution of derivative works, provided the original work is properly cited. This license requires credit be given to copyright holder and/or author, copyright and license notices be kept intact.

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