EMD-4746
CryoEM structure of calcium-bound human TMEM16K / Anoctamin 10 in detergent (2mM Ca2+, closed form)
EMD-4746
Single-particle3.47 Å
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Map released: 01/05/2019
Last modified: 22/05/2024
Sample Organism:
Homo sapiens
Sample: Anoctamin 10
Fitted models: 6r7x (Avg. Q-score: 0.516)
Deposition Authors: Pike ACW
,
Bushell SR
Sample: Anoctamin 10
Fitted models: 6r7x (Avg. Q-score: 0.516)
Deposition Authors: Pike ACW
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The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K.
Bushell SR
,
Pike ACW
,
Falzone ME
,
Rorsman NJG,
Ta CM,
Corey RA
,
Newport TD,
Christianson JC
,
Scofano LF
,
Shintre CA
,
Tessitore A,
Chu A
,
Wang Q,
Shrestha L,
Mukhopadhyay SMM
,
Love JD,
Burgess-Brown NA,
Sitsapesan R,
Stansfeld PJ
,
Huiskonen JT
,
Tammaro P
,
Accardi A
,
Carpenter EP
(2019) Nat Commun , 10 , 3956 - 3956
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(2019) Nat Commun , 10 , 3956 - 3956
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.
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.