6qpc

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Cryo-EM structure of calcium-bound mTMEM16F lipid scramblase in nanodisc

Structural highlights

6qpc is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:Ano6, Tmem16f (LK3 transgenic mice)
Experimental data:Check to display Experimental Data
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[ANO6_MOUSE] Small-conductance calcium-activated nonselective cation (SCAN) channel which acts as a regulator of phospholipid scrambling in platelets, osteoblasts and fetal thymocytes. Phospholipid scrambling results in surface exposure of phosphatidylserine which in platelets is essential to trigger the clotting system whereas in osteoblasts is essential for the deposition of hydroxyapatite during bone mineralization. Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylserine, phosphatidylcholine and galactosylceramide. Can generate outwardly rectifying chloride channel currents in airway epithelial cells and Jurkat T lymphocytes.[1] [2] [3] [4] [5]

Publication Abstract from PubMed

The lipid scramblase TMEM16F initiates blood coagulation by catalyzing the exposure of phosphatidylserine in platelets. The protein is part of a family of membrane proteins, which encompasses calcium-activated channels for ions and lipids. Here, we reveal features of murine TMEM16F (mTMEM16F) that underlie its function as a lipid scramblase and an ion channel. The cryo-EM data of mTMEM16F in absence and presence of Ca(2+) define the ligand-free closed conformation of the protein and the structure of a Ca(2+)-bound intermediate. Both conformations resemble their counterparts of the scrambling-incompetent anion channel mTMEM16A, yet with distinct differences in the region of ion and lipid permeation. In conjunction with functional data, we demonstrate the relationship between ion conduction and lipid scrambling. Although activated by a common mechanism, both functions appear to be mediated by alternate protein conformations that are at equilibrium in the ligand-bound state.

Cryo-EM structures and functional characterization of the murine lipid scramblase TMEM16F.,Alvadia C, Lim NK, Clerico Mosina V, Oostergetel GT, Dutzler R, Paulino C Elife. 2019 Feb 20;8. pii: 44365. doi: 10.7554/eLife.44365. PMID:30785399[6]

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

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References

  1. ↑ Suzuki J, Umeda M, Sims PJ, Nagata S. Calcium-dependent phospholipid scrambling by TMEM16F. Nature. 2010 Dec 9;468(7325):834-8. doi: 10.1038/nature09583. Epub 2010 Nov 24. PMID:21107324 doi:http://dx.doi.org/10.1038/nature09583
  2. ↑ Kunzelmann K, Schreiber R, Kmit A, Jantarajit W, Martins JR, Faria D, Kongsuphol P, Ousingsawat J, Tian Y. Expression and function of epithelial anoctamins. Exp Physiol. 2012 Feb;97(2):184-92. doi: 10.1113/expphysiol.2011.058206. Epub, 2011 Sep 9. PMID:21908539 doi:http://dx.doi.org/10.1113/expphysiol.2011.058206
  3. ↑ Ehlen HW, Chinenkova M, Moser M, Munter HM, Krause Y, Gross S, Brachvogel B, Wuelling M, Kornak U, Vortkamp A. Inactivation of anoctamin-6/Tmem16f, a regulator of phosphatidylserine scrambling in osteoblasts, leads to decreased mineral deposition in skeletal tissues. J Bone Miner Res. 2013 Feb;28(2):246-59. doi: 10.1002/jbmr.1751. PMID:22936354 doi:http://dx.doi.org/10.1002/jbmr.1751
  4. ↑ Yang H, Kim A, David T, Palmer D, Jin T, Tien J, Huang F, Cheng T, Coughlin SR, Jan YN, Jan LY. TMEM16F forms a Ca2+-activated cation channel required for lipid scrambling in platelets during blood coagulation. Cell. 2012 Sep 28;151(1):111-22. doi: 10.1016/j.cell.2012.07.036. PMID:23021219 doi:http://dx.doi.org/10.1016/j.cell.2012.07.036
  5. ↑ Suzuki J, Fujii T, Imao T, Ishihara K, Kuba H, Nagata S. Calcium-dependent phospholipid scramblase activity of TMEM16 protein family members. J Biol Chem. 2013 May 10;288(19):13305-16. doi: 10.1074/jbc.M113.457937. Epub, 2013 Mar 26. PMID:23532839 doi:http://dx.doi.org/10.1074/jbc.M113.457937
  6. ↑ Alvadia C, Lim NK, Clerico Mosina V, Oostergetel GT, Dutzler R, Paulino C. Cryo-EM structures and functional characterization of the murine lipid scramblase TMEM16F. Elife. 2019 Feb 20;8. pii: 44365. doi: 10.7554/eLife.44365. PMID:30785399 doi:http://dx.doi.org/10.7554/eLife.44365

Contents


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6qpc, resolution 3.50Å

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