FA Sliding as the Mechanism for the ANT1-Mediated Fatty Acid Anion Transport in Lipid Bilayers
Mitochondrial adenine nucleotide translocase (ANT) exchanges ADP for ATP to maintain energy production in the cell. Its protonophoric function in the presence of long-chain fatty acids (FA) is also recognized. Our previous results imply that proton/FA transport can be best described with the FA cycl...
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MDPI AG
2023-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/18/13701 |
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| author | Jürgen Kreiter Sanja Škulj Zlatko Brkljača Sarah Bardakji Mario Vazdar Elena E. Pohl |
| author_facet | Jürgen Kreiter Sanja Škulj Zlatko Brkljača Sarah Bardakji Mario Vazdar Elena E. Pohl |
| author_sort | Jürgen Kreiter |
| collection | DOAJ |
| description | Mitochondrial adenine nucleotide translocase (ANT) exchanges ADP for ATP to maintain energy production in the cell. Its protonophoric function in the presence of long-chain fatty acids (FA) is also recognized. Our previous results imply that proton/FA transport can be best described with the FA cycling model, in which protonated FA transports the proton to the mitochondrial matrix. The mechanism by which ANT1 transports FA anions back to the intermembrane space remains unclear. Using a combined approach involving measurements of the current through the planar lipid bilayers reconstituted with ANT1, site-directed mutagenesis and molecular dynamics simulations, we show that the FA anion is first attracted by positively charged arginines or lysines on the matrix side of ANT1 before moving along the positively charged protein–lipid interface and binding to R79, where it is protonated. We show that R79 is also critical for the competitive binding of ANT1 substrates (ADP and ATP) and inhibitors (carboxyatractyloside and bongkrekic acid). The binding sites are well conserved in mitochondrial SLC25 members, suggesting a general mechanism for transporting FA anions across the inner mitochondrial membrane. |
| first_indexed | 2024-03-10T22:41:12Z |
| format | Article |
| id | doaj.art-63ff46dfeb1c42408ee78b561fd508f7 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T22:41:12Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-63ff46dfeb1c42408ee78b561fd508f72023-11-19T11:01:58ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-09-0124181370110.3390/ijms241813701FA Sliding as the Mechanism for the ANT1-Mediated Fatty Acid Anion Transport in Lipid BilayersJürgen Kreiter0Sanja Škulj1Zlatko Brkljača2Sarah Bardakji3Mario Vazdar4Elena E. Pohl5Institute of Physiology, Pathophysiology, and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, 1210 Vienna, AustriaInstitute of Physiology, Pathophysiology, and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, 1210 Vienna, AustriaDivision of Organic Chemistry and Biochemistry, Rudjer Bošković Institute, 10000 Zagreb, CroatiaInstitute of Physiology, Pathophysiology, and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, 1210 Vienna, AustriaDepartment of Mathematics, Informatics, and Cybernetics, University of Chemistry and Technology, 166 28 Prague, Czech RepublicInstitute of Physiology, Pathophysiology, and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, 1210 Vienna, AustriaMitochondrial adenine nucleotide translocase (ANT) exchanges ADP for ATP to maintain energy production in the cell. Its protonophoric function in the presence of long-chain fatty acids (FA) is also recognized. Our previous results imply that proton/FA transport can be best described with the FA cycling model, in which protonated FA transports the proton to the mitochondrial matrix. The mechanism by which ANT1 transports FA anions back to the intermembrane space remains unclear. Using a combined approach involving measurements of the current through the planar lipid bilayers reconstituted with ANT1, site-directed mutagenesis and molecular dynamics simulations, we show that the FA anion is first attracted by positively charged arginines or lysines on the matrix side of ANT1 before moving along the positively charged protein–lipid interface and binding to R79, where it is protonated. We show that R79 is also critical for the competitive binding of ANT1 substrates (ADP and ATP) and inhibitors (carboxyatractyloside and bongkrekic acid). The binding sites are well conserved in mitochondrial SLC25 members, suggesting a general mechanism for transporting FA anions across the inner mitochondrial membrane.https://www.mdpi.com/1422-0067/24/18/13701fatty acid cycling hypothesisADP/ATP carrierAACuncoupling proteinsproton transportfatty acids anion transport |
| spellingShingle | Jürgen Kreiter Sanja Škulj Zlatko Brkljača Sarah Bardakji Mario Vazdar Elena E. Pohl FA Sliding as the Mechanism for the ANT1-Mediated Fatty Acid Anion Transport in Lipid Bilayers International Journal of Molecular Sciences fatty acid cycling hypothesis ADP/ATP carrier AAC uncoupling proteins proton transport fatty acids anion transport |
| title | FA Sliding as the Mechanism for the ANT1-Mediated Fatty Acid Anion Transport in Lipid Bilayers |
| title_full | FA Sliding as the Mechanism for the ANT1-Mediated Fatty Acid Anion Transport in Lipid Bilayers |
| title_fullStr | FA Sliding as the Mechanism for the ANT1-Mediated Fatty Acid Anion Transport in Lipid Bilayers |
| title_full_unstemmed | FA Sliding as the Mechanism for the ANT1-Mediated Fatty Acid Anion Transport in Lipid Bilayers |
| title_short | FA Sliding as the Mechanism for the ANT1-Mediated Fatty Acid Anion Transport in Lipid Bilayers |
| title_sort | fa sliding as the mechanism for the ant1 mediated fatty acid anion transport in lipid bilayers |
| topic | fatty acid cycling hypothesis ADP/ATP carrier AAC uncoupling proteins proton transport fatty acids anion transport |
| url | https://www.mdpi.com/1422-0067/24/18/13701 |
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