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The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K
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(2019) The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K. Nature Communications, 10 (1). 3956 . doi:10.1038/s41467-019-11753-1
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Official URL: http://dx.doi.org/10.1038/s41467-019-11753-1
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.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Divisions: | Faculty of Science > Life Sciences (2010- ) | ||||
| Journal or Publication Title: | Nature Communications | ||||
| Publisher: | Nature Publishing Group | ||||
| ISSN: | 2041-1723 | ||||
| Official Date: | 2 September 2019 | ||||
| Dates: |
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| Date of first compliant deposit: | 1 October 2019 | ||||
| Volume: | 10 | ||||
| Number: | 1 | ||||
| Article Number: | 3956 | ||||
| DOI: | 10.1038/s41467-019-11753-1 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Open Access |
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