Insertases Scramble Lipids: Molecular Simulations of MTCH2

Abstract

Scramblases play a pivotal role in facilitating bidirectional lipid transport across cell membranes, thereby influencing lipid metabolism, membrane homeostasis, and cellular signaling. MTCH2, a mitochondrial outer membrane protein insertase, has a membrane-spanning hydrophilic groove resembling those that form the lipid transit pathway in known scramblases. Employing both coarse-grained and atomistic molecular dynamics simulations, we show that MTCH2 significantly reduces the free energy barrier for lipid movement along the groove and therefore can indeed function as a scramblase. Notably, the scrambling rate of MTCH2 in silico is similar to that of VDAC, a recently discovered scramblase of the outer mitochondrial membrane, suggesting a potential complementary physiological role for these mitochondrial proteins. Finally, our findings suggest that other insertases which possess a hydrophilic path across the membrane like MTCH2, can also function as scramblases. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC="FIGDIR/small/553169v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@e78668org.highwire.dtl.DTLVardef@292ce0org.highwire.dtl.DTLVardef@1413077org.highwire.dtl.DTLVardef@d4e29b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIScrambling activity of MTCH2 identified using computer simulations C_LIO_LIMTCH2 may act redundantly with VDAC as outer mitochondrial membrane scram-blase C_LIO_LIInsertases and scramblases may share a common functional mechanism C_LI