Lipids surf the groove in scramblases

Abstract

Lipid membranes have many fundamental roles in biology because they establish amphipathic and highly dynamic boundaries around cellular compartments. The plasma membrane and intracellular membranes are primarily composed of phospholipids that have a hydrophilic headgroup and a hydrophobic tail, enabling them to assemble into lipid bilayers (Fig. 1). Phospholipids differ greatly in their structure, and although they can rapidly diffuse within the plane of the membrane, they typically have asymmetrical distributions in the outer and inner leaflets of the bilayer, enabling them to play important roles in cellular signaling (1). For example, active transporters translocate phosphatidylserine (PS) into the inner leaflet of the plasma membrane to generate a pronounced asymmetry, and lipid scramblases catalyze the passive diffusion of PS into the outer leaflet, triggering blood coagulation in platelets or marking cells for phagocytosis following apoptosis (2). Although the mechanism by which ATPases transport lipids across membranes has been studied for some time, the mechanism by which scramblases catalyze diffusion of lipids across the membrane is unclear (3, 4). In PNAS, Malvezzi et al. (5) study the mechanisms of Ca2+-activated lipid scrambling mediated by TMEM16 proteins (6⇓⇓⇓–10) and Ca2+-independent scrambling mediated by opsin, a class A or rhodopsin-like G-protein—coupled receptor (11⇓–13). Fig. 1. Mechanisms of lipid scrambling. The credit card model (left protomer) and the out-of-the-groove model (right protomer) are depicted in the protomer of a TMEM16 dimer. In the credit card model, lipids diffuse through the groove at the protein–lipid interface, whereas in the out-of-the-groove model, the groove locally deforms the membrane by thinning the membrane (indicated by blue arrows) to lower the barrier for lipids to move from one leaflet to another. The nonselective permeation of ions is depicted as occurring within the groove. One model that … [↵][1]1To whom correspondence should be addressed. Email: kenton.swartz{at}nih.gov. [1]: #xref-corresp-1-1