Membrane proteins are crucial for maintaining membrane homeostasis, supporting organelle function, and mediating dynamic cellular responses. These proteins can be classified based on their function; for example, scramblases symmetrize lipid distribution within the membrane bilayer by facilitating lipid flip-flop; insertases are essential for membrane protein integration; and translocases enable the transport of macromolecules across membranes. By investigating their mechanisms of action, we demonstrate that some of these proteins share a common mechanism of action via local membrane thinning, which suggests a possible convergence in function. In particular, we identified a novel function of the mitochondrial voltage-dependent anion channel (VDAC) as the first scramblase with a β-barrel structure. It facilitates lipid scrambling at the dimer interface by locally thinning the membrane. A similar thinning-mediated mechanism was observed in a structurally unrelated protein with a helical architecture, mitochondrial carrier homolog 2 (MTCH2), which is recognized for its insertase function via local membrane thinning. This local thinning was similar to VDAC and indeed also the observed lipid scrambling rates were similar. Finally, we observed the same mechanism of local membrane thinning and lipid scrambling in a de novo-designed translocase. Based on these findings, we propose that proteins capable of locally thinning membranes may act simultaneously as scramblases, insertases, and translocases by lowering the energetic barrier for transmembrane transport.
Vacha et al. (Sun,) studied this question.