6R7X

CryoEM structure of calcium-bound human TMEM16K / Anoctamin 10 in detergent (2mM Ca2+, closed form)

Summary for 6R7X

• Entry DOI: 10.2210/pdb6r7x/pdb
• EMDB information: 4746
• Descriptor: Anoctamin-10, CALCIUM ION, 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE, ... (4 entities in total)
• Functional Keywords: membrane protein, calcium activation, transport protein, lipid transport, structural genomics, structural genomics consortium, sgc
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 166304.57

Authors

Pike, A.C.W.,Bushell, S.R.,Shintre, C.A.,Tessitore, A.,Baronina, A.,Chu, A.,Mukhopadhyay, S.,Shrestha, L.,Chalk, R.,Burgess-Brown, N.A.,Love, J.,Huiskonen, J.T.,Edwards, A.M.,Arrowsmith, C.H.,Bountra, C.,Carpenter, E.P.,Structural Genomics Consortium (SGC) (deposition date: 2019-03-29, release date: 2019-05-01, Last modification date: 2024-05-22)

Primary citation

Bushell, S.R.,Pike, A.C.W.,Falzone, M.E.,Rorsman, N.J.G.,Ta, C.M.,Corey, R.A.,Newport, T.D.,Christianson, J.C.,Scofano, L.F.,Shintre, C.A.,Tessitore, A.,Chu, A.,Wang, Q.,Shrestha, L.,Mukhopadhyay, S.M.M.,Love, J.D.,Burgess-Brown, N.A.,Sitsapesan, R.,Stansfeld, P.J.,Huiskonen, J.T.,Tammaro, P.,Accardi, A.,Carpenter, E.P.
The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K.
Nat Commun, 10:3956-3956, 2019

PubMed 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.

PubMed: 31477691
DOI: 10.1038/s41467-019-11753-1

Experimental method

ELECTRON MICROSCOPY (3.47 Å)