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

• DOI: 10.7554/elife.43229
• Publication Date: 2019-01-16T13:02:19Z
• Authors: Maria E Falzone; Jan Rheinberger; Byoung-Cheol Lee; Thasin Peyear; Linda Sasset; Ashleigh M Raczko...; Edward T Eng; Annarita Di Lorenzo; Olaf S Andersen; Crina M Nimigean; Alessio Accardi
• Keywords: Phospholipid scramblase; Flippase

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