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Elife. 2019 Jan 16;8. pii: e43229. doi: 10.7554/eLife.43229.

Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase.

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Department of Biochemistry, Weill Cornell Medical College, New York, United States.
Department of Anesthesiology, Weill Cornell Medical College, New York, United States.
Department of Structure and Function on Neural Network, Korea Brain Research Institute, Deagu, Republic of Korea.
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, United States.
Department of Pathology, Weill Cornell Medical College, New York, United States.
Simons Electron Microscopy Center, New York Structural Biology Center, New York, United States.


The lipid distribution of plasma membranes of eukaryotic cells is asymmetric and phospholipid scramblases disrupt this asymmetry by mediating the rapid, nonselective transport of lipids down their concentration gradients. As a result, phosphatidylserine is exposed to the outer leaflet of membrane, an important step in extracellular signaling networks controlling processes such as apoptosis, blood coagulation, membrane fusion and repair. Several TMEM16 family members have been identified as Ca2+-activated scramblases, but the mechanisms underlying their Ca2+-dependent gating and their effects on the surrounding lipid bilayer remain poorly understood. Here, we describe three high-resolution cryo-electron microscopy structures of a fungal scramblase from Aspergillus fumigatus, afTMEM16, reconstituted in lipid nanodiscs. These structures reveal that Ca2+-dependent activation of the scramblase entails global rearrangement of the transmembrane and cytosolic domains. These structures, together with functional experiments, suggest that activation of the protein thins the membrane near the transport pathway to facilitate rapid transbilayer lipid movement.


S. cerevisiae; Scrambling; membrane channels; membrane structure; molecular biophysics; phospholipids; structural biology

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