Hexokinase-I directly binds to a charged membrane-buried glutamate of mitochondrial VDAC1 and VDAC2
Abstract Binding of hexokinase HKI to mitochondrial voltage-dependent anion channels (VDACs) has far-reaching physiological implications. However, the structural basis of this interaction is unclear. Combining computer simulations with experiments in cells, we here show that complex assembly relies...
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| Format: | Article |
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Nature Portfolio
2025-02-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07551-9 |
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| author | Sebastian Bieker Michael Timme Nils Woge Dina G. Hassan Chelsea M. Brown Siewert J. Marrink Manuel N. Melo Joost C. M. Holthuis |
| author_facet | Sebastian Bieker Michael Timme Nils Woge Dina G. Hassan Chelsea M. Brown Siewert J. Marrink Manuel N. Melo Joost C. M. Holthuis |
| author_sort | Sebastian Bieker |
| collection | DOAJ |
| description | Abstract Binding of hexokinase HKI to mitochondrial voltage-dependent anion channels (VDACs) has far-reaching physiological implications. However, the structural basis of this interaction is unclear. Combining computer simulations with experiments in cells, we here show that complex assembly relies on intimate contacts between the N-terminal α-helix of HKI and a charged membrane-buried glutamate on the outer wall of VDAC1 and VDAC2. Protonation of this residue blocks complex formation in silico while acidification of the cytosol causes a reversable release of HKI from mitochondria. Membrane insertion of HKI occurs adjacent to the bilayer-facing glutamate where a pair of polar channel residues mediates a marked thinning of the cytosolic leaflet. Disrupting the membrane thinning capacity of VDAC1 dramatically impairs its ability to bind HKI in silico and in cells. Our data reveal key topological and mechanistic insights into HKI-VDAC complex assembly that may benefit the development of therapeutics to counter pathogenic imbalances in this process. |
| format | Article |
| id | doaj-art-e5622aec85b64030840269ad066dc8c7 |
| institution | DOAJ |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-e5622aec85b64030840269ad066dc8c72025-08-20T03:01:00ZengNature PortfolioCommunications Biology2399-36422025-02-018111710.1038/s42003-025-07551-9Hexokinase-I directly binds to a charged membrane-buried glutamate of mitochondrial VDAC1 and VDAC2Sebastian Bieker0Michael Timme1Nils Woge2Dina G. Hassan3Chelsea M. Brown4Siewert J. Marrink5Manuel N. Melo6Joost C. M. Holthuis7Molecular Cell Biology Division, Department of Biology/Chemistry, University of OsnabrückMolecular Cell Biology Division, Department of Biology/Chemistry, University of OsnabrückMolecular Cell Biology Division, Department of Biology/Chemistry, University of OsnabrückMolecular Cell Biology Division, Department of Biology/Chemistry, University of OsnabrückGroningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da RepúblicaMolecular Cell Biology Division, Department of Biology/Chemistry, University of OsnabrückAbstract Binding of hexokinase HKI to mitochondrial voltage-dependent anion channels (VDACs) has far-reaching physiological implications. However, the structural basis of this interaction is unclear. Combining computer simulations with experiments in cells, we here show that complex assembly relies on intimate contacts between the N-terminal α-helix of HKI and a charged membrane-buried glutamate on the outer wall of VDAC1 and VDAC2. Protonation of this residue blocks complex formation in silico while acidification of the cytosol causes a reversable release of HKI from mitochondria. Membrane insertion of HKI occurs adjacent to the bilayer-facing glutamate where a pair of polar channel residues mediates a marked thinning of the cytosolic leaflet. Disrupting the membrane thinning capacity of VDAC1 dramatically impairs its ability to bind HKI in silico and in cells. Our data reveal key topological and mechanistic insights into HKI-VDAC complex assembly that may benefit the development of therapeutics to counter pathogenic imbalances in this process.https://doi.org/10.1038/s42003-025-07551-9 |
| spellingShingle | Sebastian Bieker Michael Timme Nils Woge Dina G. Hassan Chelsea M. Brown Siewert J. Marrink Manuel N. Melo Joost C. M. Holthuis Hexokinase-I directly binds to a charged membrane-buried glutamate of mitochondrial VDAC1 and VDAC2 Communications Biology |
| title | Hexokinase-I directly binds to a charged membrane-buried glutamate of mitochondrial VDAC1 and VDAC2 |
| title_full | Hexokinase-I directly binds to a charged membrane-buried glutamate of mitochondrial VDAC1 and VDAC2 |
| title_fullStr | Hexokinase-I directly binds to a charged membrane-buried glutamate of mitochondrial VDAC1 and VDAC2 |
| title_full_unstemmed | Hexokinase-I directly binds to a charged membrane-buried glutamate of mitochondrial VDAC1 and VDAC2 |
| title_short | Hexokinase-I directly binds to a charged membrane-buried glutamate of mitochondrial VDAC1 and VDAC2 |
| title_sort | hexokinase i directly binds to a charged membrane buried glutamate of mitochondrial vdac1 and vdac2 |
| url | https://doi.org/10.1038/s42003-025-07551-9 |
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