6r7x

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

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Structural highlights

6r7x is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.47Å
Ligands:CA, PC1, UMQ
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ANO10_HUMAN Adult-onset autosomal recessive cerebellar ataxia. The disease is caused by mutations affecting the gene represented in this entry.

Function

ANO10_HUMAN Does not exhibit calcium-activated chloride channel (CaCC) activity. Can inhibit the activity of ANO1.[1] [2]

Publication Abstract from PubMed

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.

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 Nat Commun. 2019 Sep 2;10(1):3956. doi: 10.1038/s41467-019-11753-1. PMID:31477691[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Schreiber R, Uliyakina I, Kongsuphol P, Warth R, Mirza M, Martins JR, Kunzelmann K. Expression and function of epithelial anoctamins. J Biol Chem. 2010 Mar 5;285(10):7838-45. doi: 10.1074/jbc.M109.065367. Epub 2010 , Jan 7. PMID:20056604 doi:http://dx.doi.org/10.1074/jbc.M109.065367
  2. ↑ Tian Y, Schreiber R, Kunzelmann K. Anoctamins are a family of Ca2+-activated Cl- channels. J Cell Sci. 2012 Nov 1;125(Pt 21):4991-8. doi: 10.1242/jcs.109553. Epub 2012 Sep , 3. PMID:22946059 doi:http://dx.doi.org/10.1242/jcs.109553
  3. ↑ 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. The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K. Nat Commun. 2019 Sep 2;10(1):3956. doi: 10.1038/s41467-019-11753-1. PMID:31477691 doi:http://dx.doi.org/10.1038/s41467-019-11753-1

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