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Insertases Scramble Lipids: Molecular Simulations of MTCH2
Open accessPreprint — published as 10.1016/j.str.2024.01.012 · Paper page
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: Highlights: Scrambling activity of MTCH2 identified using computer simulations MTCH2 may act redundantly with VDAC as outer mitochondrial membrane scram-blase Insertases and scramblases may share a common functional mechanism
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Metadata
- Authors
- Bartoš, L., Menon, A. K., & Vácha, R.
- Affiliations
- Masaryk University (CZ)
- Weill Cornell Medicine (US)
- Corresponding author
- Vácha, Robert
- Venue
- Structure
- Publisher
- openRxiv
- Published
- 2023-08-14
- Volume
- 32
- Issue
- 4
- Pages
- 505-510.e4
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC10462046
- OpenAlex
- W4391934091
- Cited by
- 42
- References
- 1
- Citations by year
- 2026: 6 · 2025: 24 · 2024: 7 · 2023: 5
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Structure (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Veřejné služby Informačního systému (Masarykiana Brunensis Universitas) (submittedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by)
- Funders
- European High Performance Computing Joint Undertaking
- European Commission (LX22NPO5103, HORIZON2020, 101001470, 90254)
- Ministerstvo Školství, Mládeže a Tělovýchovy (90254), ID: 90254, LX22NPO5103)
- China Scholarship Council
- National Institutes of Health (1r21ns119779-01)
- Horizon 2020 Framework Programme
- European Research Council
- Horizon 2020
- National Supercomputing Center, Korea Institute of Science and Technology Information
- National Institute of Neurological Disorders and Stroke (R21 NS119779)
- H2020 European Research Council (101001470)
- NextGenerationEU
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- MTCH2, scramblase, lipid transport, mitochondrial outer membrane, activation barrier, voltage-dependent anion channel, membrane protein function, lipid metabolism
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