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 voltage-dependent anion channel (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.

CEITEC Central European Institute of Technology Masaryk University Kamenice 5 625 00 Brno Czech Republic; National Centre for Biomolecular Research Faculty of Science Masaryk University Kamenice 5 625 00 Brno Czech Republic

CEITEC Central European Institute of Technology Masaryk University Kamenice 5 625 00 Brno Czech Republic; National Centre for Biomolecular Research Faculty of Science Masaryk University Kamenice 5 625 00 Brno Czech Republic; Department of Condensed Matter Physics Faculty of Science Masaryk University Kotlářská 2 611 37 Brno Czech Republic

Department of Biochemistry Weill Cornell Medical College New York NY 10065 USA

bioRxiv. 2023 Dec 02:2023.08.14.553169. doi: 10.1101/2023.08.14.553169. PubMed

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Lipid Scrambling Pathways in the Sec61 Translocon Complex

Optimizing properties of translocation-enhancing transmembrane proteins

Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase