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Cryo-EM structure of Ca2+-bound mTMEM16F N562A mutant in Digitonin closed/closedCryo-EM structure of Ca2+-bound mTMEM16F N562A mutant in Digitonin closed/closed
Structural highlights
FunctionANO6_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 PubMedTMEM16F, a member of the conserved TMEM16 family, plays a central role in the initiation of blood coagulation and the fusion of trophoblasts. The protein mediates passive ion and lipid transport in response to an increase in intracellular Ca(2+). However, the mechanism of how the protein facilitates both processes has remained elusive. Here we investigate the basis for TMEM16F activation. In a screen of residues lining the proposed site of conduction, we identify mutants with strongly activating phenotype. Structures of these mutants determined herein by cryo-electron microscopy show major rearrangements leading to the exposure of hydrophilic patches to the membrane, whose distortion facilitates lipid diffusion. The concomitant opening of a pore promotes ion conduction in the same protein conformation. Our work has revealed a mechanism that is distinct for this branch of the family and that will aid the development of a specific pharmacology for a promising drug target. Structural basis for the activation of the lipid scramblase TMEM16F.,Arndt M, Alvadia C, Straub MS, Clerico Mosina V, Paulino C, Dutzler R Nat Commun. 2022 Nov 5;13(1):6692. doi: 10.1038/s41467-022-34497-x. PMID:36335104[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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