6p48

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Cryo-EM structure of calcium-bound TMEM16F in nanodisc with supplement of PIP2 in Cl1

Structural highlights

6p48 is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.2Å
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

As a Ca(2+)-activated lipid scramblase and ion channel that mediates Ca(2+) influx, TMEM16F relies on both functions to facilitate extracellular vesicle generation, blood coagulation, and bone formation. How a bona fide ion channel scrambles lipids remains elusive. Our structural analyses revealed the coexistence of an intact channel pore and PIP2-dependent protein conformation changes leading to membrane distortion. Correlated to the extent of membrane distortion, many tightly bound lipids are slanted. Structure-based mutagenesis studies further reveal that neutralization of some lipid-binding residues or those near membrane distortion specifically alters the onset of lipid scrambling, but not Ca(2+) influx, thus identifying features outside of channel pore that are important for lipid scrambling. Together, our studies demonstrate that membrane distortion does not require open hydrophilic grooves facing the membrane interior and provide further evidence to suggest separate pathways for lipid scrambling and ion permeation.

Cryo-EM Studies of TMEM16F Calcium-Activated Ion Channel Suggest Features Important for Lipid Scrambling.,Feng S, Dang S, Han TW, Ye W, Jin P, Cheng T, Li J, Jan YN, Jan LY, Cheng Y Cell Rep. 2019 Jul 9;28(2):567-579.e4. doi: 10.1016/j.celrep.2019.06.023. PMID:31291589[6]

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

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See Also

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. ↑ Feng S, Dang S, Han TW, Ye W, Jin P, Cheng T, Li J, Jan YN, Jan LY, Cheng Y. Cryo-EM Studies of TMEM16F Calcium-Activated Ion Channel Suggest Features Important for Lipid Scrambling. Cell Rep. 2019 Jul 9;28(2):567-579.e4. doi: 10.1016/j.celrep.2019.06.023. PMID:31291589 doi:http://dx.doi.org/10.1016/j.celrep.2019.06.023

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6p48, resolution 3.20Å

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