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Talk by Alessio Accardi

Title: "In or out…of the groove? How the TMEM16s flip lipids"
Occasion: SFB Special Seminar
Start: 10.06.2024 12 p.m.
Location: CellNanOs, 38/201

About the speaker: Prof. Dr. Alessio Accardi conducts research at the Weill Cornell Medicine Department of Biochemistry, New York

Abstract of the talk: Phospholipid scramblases mediate the rapid movement of lipids between membrane leaflets, a key step in establishing and maintaining membrane homeostasis in all eukaryotic cells and their organelles. The most extensively studied and best understood family of scramblases are the Ca2+-activated TMEM16s. Disruption of TMEM16 function leads to a variety of pathological states, such as defective blood coagulation, impaired membrane fusion and repair in muscle and bone, as well as neurological disorders. However, how these proteins catalyze the transbilayer movement of lipids remains poorly understood. Early work supported the view that these proteins provided a hydrophilic, membrane-exposed groove through which the lipid headgroups could permeate. I will discuss our recent work where using a combination of structural and functional experiments we proposed an alternative mechanism where the TMEM16s distort and thin the membrane near the groove to facilitate lipid scrambling. Using cryoEM of fungal TMEM16s we directly visualized the differential association of lipids with an open and with a closed groove. Functional experiments pinpoint lipid-protein interaction sites critical for closed groove scrambling. Unexpectedly, we show that the choice of nanodisc scaffold protein and lipids affects the conformations of nhTMEM16 and their distribution, highlighting a key role of these factors in cryo-EM structure determination.