Journal article
The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K
- Abstract:
- Membranes in cells have defined distributions of lipids in each leaflet, controlled by lipid scramblases and flip/floppases. However, for some intracellular membranes such as the endoplasmic reticulum (ER) the scramblases have not been identified. Members of the TMEM16 family have either lipid scramblase or chloride channel activity. Although TMEM16K is widely distributed and associated with the neurological disorder autosomal recessive spinocerebellar ataxia type 10 (SCAR10), its location in cells, function and structure are largely uncharacterised. Here we show that TMEM16K is an ER-resident lipid scramblase with a requirement for short chain lipids and calcium for robust activity. Crystal structures of TMEM16K show a scramblase fold, with an open lipid transporting groove. Additional cryo-EM structures reveal extensive conformational changes from the cytoplasmic to the ER side of the membrane, giving a state with a closed lipid permeation pathway. Molecular dynamics simulations showed that the open-groove conformation is necessary for scramblase activity.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 5.3MB, Terms of use)
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- Publisher copy:
- 10.1038/s41467-019-11753-1
Authors
- Publisher:
- Springer Nature
- Journal:
- Nature Communications More from this journal
- Volume:
- 10
- Article number:
- 3956 (2019)
- Publication date:
- 2019-09-02
- Acceptance date:
- 2019-08-01
- DOI:
- EISSN:
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2041-1723
- Pmid:
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31477691
- Language:
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English
- Keywords:
- Pubs id:
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pubs:1049283
- UUID:
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uuid:358f687c-d7da-45fe-aa8f-bd8c91202ecc
- Local pid:
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pubs:1049283
- Source identifiers:
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1049283
- Deposit date:
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2019-09-18
Terms of use
- Copyright date:
- 2019
- Notes:
- © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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