Abstract
In eukaryotic cells, the composition and distribution of the phospholipid constituents of the membrane is tightly regulated by the activity of dedicated enzymes, flippases, floppases and scramblases. TMEM16 scramblases dissipate the plasma membrane lipid asymmetry to activate multiple eukaryotic cellular pathways. It was proposed that lipid headgroups move between leaflets through a membrane-spanning hydrophilic groove via a so-called “credit-card” mechanism where the hydrophilic head groups move through an open groove while their hydrophobic tails remain in the membrane.
Highlights
Biological membranes play a fundamental role in many cellular signaling pathways as they define the physical boundaries of cellular compartments and actively modulate the function of integral and membrane-associated proteins
Dysregulation of TMEM16 scramblase activity can have disastrous consequences, as both gain- and loss- of function mutations have been associated with disorders of blood, brain, bone and muscle [3,8,9,10,11]
Moderate resolution structures of the fungal afTMEM16 and nhTMEM16 in nanodiscs showed these scramblases thin the membrane near the groove [15,17], suggesting that membrane thinning at an open pathway might be important for lipid scrambling 15
Summary
Biological membranes play a fundamental role in many cellular signaling pathways as they define the physical boundaries of cellular compartments and actively modulate the function of integral and membrane-associated proteins. Moderate resolution structures of the fungal afTMEM16 and nhTMEM16 in nanodiscs showed these scramblases thin the membrane near the groove [15,17], suggesting that membrane thinning at an open pathway might be important for lipid scrambling 15. Our structure allows the direct visualization of lipids associated with the protein at the open groove and reveals that afTMEM16 thins the membrane at the open pathway by ~50%.
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