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.

CEITEC Central European Institute of Technology Masaryk University Kamenice 753 5 625 00 Brno Czech Republic

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

Department of Condensed Matter Physics Faculty of Science Masaryk University Kotlarska 267 2 611 37 Brno Czech Republic

National Centre for Biomolecular Research Faculty of Science Masaryk University Kamenice 753 5 625 00 Brno Czech Republic

Structure. 2024 Apr 4;32(4):505-510.e4. doi: 10.1016/j.str.2024.01.012. PubMed

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