Structural basis for phospholipid scrambling in the TMEM16 family

Abstract

Upon activation, lipid scramblases dissipate the lipid asymmetry of membranes, in an ATP-independent manner, by catalyzing flip-flop of lipids between the leaflets. The molecular identities of these proteins long remained obscure, but in recent years the TMEM16 family of proteins has been found to constitute Ca²⁺-activated scramblases. Recently, the X-ray structure of a fungal TMEM16 homologue has provided insight into the architecture of this protein family and into potential scrambling mechanisms. The protein forms homodimers with each subunit containing a membrane-spanning hydrophilic cleft. This region is of sufficient size to harbor polar headgroups on their way across the membrane and thus may lower the energetic barrier for the diffusion of lipids between the two leaflets of the bilayer. A regulatory Ca²⁺ binding site located within the membrane adjacent to this hydrophobic cleft is responsible for activation by yet unknown mechanisms.