The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K.
Amino Acid Sequence
Animals
Anoctamins
/ chemistry
COS Cells
Calcium
/ chemistry
Cell Line, Tumor
Chlorocebus aethiops
Crystallography, X-Ray
Endoplasmic Reticulum
/ metabolism
HEK293 Cells
Humans
Lipids
/ chemistry
Molecular Dynamics Simulation
Phospholipid Transfer Proteins
/ chemistry
Sequence Homology, Amino Acid
Sf9 Cells
Spodoptera
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 09 2019
02 09 2019
Historique:
received:
14
10
2018
accepted:
01
08
2019
entrez:
4
9
2019
pubmed:
4
9
2019
medline:
31
12
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31477691
doi: 10.1038/s41467-019-11753-1
pii: 10.1038/s41467-019-11753-1
pmc: PMC6718402
doi:
Substances chimiques
ANO10 protein, human
0
Anoctamins
0
Lipids
0
Phospholipid Transfer Proteins
0
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3956Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/P01948X/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/I019855/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : P41 GM103311
Pays : United States
Organisme : British Heart Foundation
ID : FS/17/45/33102
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : T32 GM008539
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM106717
Pays : United States
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