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"... investigators have revealed the detailed workings of a cell membrane protein that has essential roles in all animals. The discovery could lead to new therapeutic strategies for blood coagulation disorders, cancers and other conditions in which the protein, called a TMEM16 scramblase, works abnormally.
Scramblases operate within cell membranes, where they alter or “scramble” the normal layered arrangement of lipid molecules – an essential step in many biological processes. The scramblase TMEM16F also works as an ion channel, allowing small, charged molecules such as potassium or chloride ions through the membrane. ...
the researchers at last attained this goal by embedding the protein in liposomes – tiny lipid capsules – which allowed them to image its active and inactive structures at near-atomic-scale resolution. ...
TMEM16F’s rearrangement of cell membrane lipids enables platelet cells to clump together to make blood coagulate, and a mutation affecting the scramblase underlies Scott syndrome, a hemophilia-like bleeding disorder.
The protein is also involved in the formation of the placenta in pregnancy, bone development and immune functions; and it is exploited or suppressed in various cancers and infections. ..."
From the abstract:
"The ubiquitous transmembrane protein 16F (TMEM16F) Ca2+-activated channel and scramblase catalyzes phosphatidylserine externalization to enable blood coagulation, membrane fusion and brain immune surveillance.
Despite its importance, the molecular mechanisms underlying TMEM16F activation remain poorly understood.
Here, we obtained high-resolution cryo-electron microscopy structures of TMEM16F active in liposomes. In high-activity conditions, TMEM16F adopts two conformations, the canonical Ca2+-bound closed state and one where the upward rotation of the cytosolic domain leads to an X-shaped groove that forms a transmembrane pore and locally thins the membrane.
Using mutagenesis, functional assays and molecular dynamics simulations, we show that the X-shaped groove is active and mediates nonselective ion flux and lipid scrambling through distinct pathways; ions move within the protein-delimited pore, whereas lipids skirt the X-shaped groove.
Our findings provide a complete picture of TMEM16F Ca2+-dependent gating and demonstrate that imaging membrane proteins in a native-like environment can allow capturing otherwise inaccessible active states."
Fig. 1: Structure of purified TMEM16F reconstituted in liposomes.
Fig. 5: Activation of TMEM16F.
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