Its own architect: Flipping cardiolipin synthase.

Abstract

Current dogma assumes that lipid asymmetry in biological membranes is actively maintained and dispensable for cell viability. The inner (cytoplasmic) membrane (IM) of <i>Escherichia coli</i> is asymmetric. However, the molecular mechanism that maintains this uneven distribution is unknown. We engineered a conditionally lethal phosphatidylethanolamine (PE)-deficient mutant in which the presence of cardiolipin (CL) on the periplasmic leaflet of the IM is essential for viability, revealing a mechanism that provides CL on the desired leaflet of the IM. CL synthase (ClsA) flips its catalytic cytoplasmic domain upon depletion of PE to supply nonbilayer-prone CL in the periplasmic leaflet of the IM for cell viability. In the presence of a physiological amount of PE, osmotic down-shock induces a topological inversion of ClsA, establishing the biological relevance of membrane protein reorientations in wild-type cells. These findings support a flippase-less mechanism for maintaining membrane lipid asymmetry in biogenic membranes by self-organization of a lipid-synthesizing enzyme.