LAT1 (SLC7A5) catalyzes copper(histidinate) transport switching from antiport to uniport mechanism
Summary: LAT1 (SLC7A5) is one of the most studied membrane transporters due to its relevance to physiology in supplying essential amino acids to brain and fetus, and to pathology being linked to nervous or embryo alterations; moreover, LAT1 over-expression is always associated with cancer developmen...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-10-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223018151 |
| _version_ | 1797647873738801152 |
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| author | Raffaella Scanga Mariafrancesca Scalise Nadia Marino Francesco Parisi Donatella Barca Michele Galluccio Chiara Brunocilla Lara Console Cesare Indiveri |
| author_facet | Raffaella Scanga Mariafrancesca Scalise Nadia Marino Francesco Parisi Donatella Barca Michele Galluccio Chiara Brunocilla Lara Console Cesare Indiveri |
| author_sort | Raffaella Scanga |
| collection | DOAJ |
| description | Summary: LAT1 (SLC7A5) is one of the most studied membrane transporters due to its relevance to physiology in supplying essential amino acids to brain and fetus, and to pathology being linked to nervous or embryo alterations; moreover, LAT1 over-expression is always associated with cancer development. Thus, LAT1 is exploited as a pro-drug vehicle and as a target for anti-cancer therapy. We here report the identification of a new substrate with pathophysiological implications, i.e., Cu-histidinate, and an unconventional uniport mechanism exploited for the Cu-histidinate transport. Crystals of the monomeric species Cu(His)2 were obtained in our experimental conditions and the actual transport of the complex was evaluated by a combined strategy of bioinformatics, site-directed mutagenesis, radiolabeled transport, and mass spectrometry analysis. The LAT1-mediated transport of Cu(His)2 may have profound implications for both the treatment of copper dysmetabolism diseases, such as the rare Menkes disease, and of cancer as an alternative to platinum-based therapies. |
| first_indexed | 2024-03-11T15:22:56Z |
| format | Article |
| id | doaj.art-2c6b32186c104dc4b75d4121490c9b2f |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-11T15:22:56Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-2c6b32186c104dc4b75d4121490c9b2f2023-10-28T05:08:14ZengElsevieriScience2589-00422023-10-012610107738LAT1 (SLC7A5) catalyzes copper(histidinate) transport switching from antiport to uniport mechanismRaffaella Scanga0Mariafrancesca Scalise1Nadia Marino2Francesco Parisi3Donatella Barca4Michele Galluccio5Chiara Brunocilla6Lara Console7Cesare Indiveri8Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, 87036 Arcavacata di Rende, ItalyDepartment DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, 87036 Arcavacata di Rende, ItalyMAT-INLAB (Laboratorio di Materiali Molecolari Inorganici), Department of Chemistry and Chemical Technologies (CTC), University of Calabria—UNICAL, Via P. Bucci, 87036 Arcavacata di Rende, ItalyMAT-INLAB (Laboratorio di Materiali Molecolari Inorganici), Department of Chemistry and Chemical Technologies (CTC), University of Calabria—UNICAL, Via P. Bucci, 87036 Arcavacata di Rende, ItalyDepartment DiBEST (Biologia, Ecologia e Scienze della Terra), 87036 Arcavacata di Rende, ItalyDepartment DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, 87036 Arcavacata di Rende, ItalyDepartment DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, 87036 Arcavacata di Rende, ItalyDepartment DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, 87036 Arcavacata di Rende, ItalyDepartment DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, 87036 Arcavacata di Rende, Italy; CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), 70126 Bari, Italy; Corresponding authorSummary: LAT1 (SLC7A5) is one of the most studied membrane transporters due to its relevance to physiology in supplying essential amino acids to brain and fetus, and to pathology being linked to nervous or embryo alterations; moreover, LAT1 over-expression is always associated with cancer development. Thus, LAT1 is exploited as a pro-drug vehicle and as a target for anti-cancer therapy. We here report the identification of a new substrate with pathophysiological implications, i.e., Cu-histidinate, and an unconventional uniport mechanism exploited for the Cu-histidinate transport. Crystals of the monomeric species Cu(His)2 were obtained in our experimental conditions and the actual transport of the complex was evaluated by a combined strategy of bioinformatics, site-directed mutagenesis, radiolabeled transport, and mass spectrometry analysis. The LAT1-mediated transport of Cu(His)2 may have profound implications for both the treatment of copper dysmetabolism diseases, such as the rare Menkes disease, and of cancer as an alternative to platinum-based therapies.http://www.sciencedirect.com/science/article/pii/S2589004223018151ChemistryInorganic chemistryMolecular inorganic chemistryBiochemistry |
| spellingShingle | Raffaella Scanga Mariafrancesca Scalise Nadia Marino Francesco Parisi Donatella Barca Michele Galluccio Chiara Brunocilla Lara Console Cesare Indiveri LAT1 (SLC7A5) catalyzes copper(histidinate) transport switching from antiport to uniport mechanism iScience Chemistry Inorganic chemistry Molecular inorganic chemistry Biochemistry |
| title | LAT1 (SLC7A5) catalyzes copper(histidinate) transport switching from antiport to uniport mechanism |
| title_full | LAT1 (SLC7A5) catalyzes copper(histidinate) transport switching from antiport to uniport mechanism |
| title_fullStr | LAT1 (SLC7A5) catalyzes copper(histidinate) transport switching from antiport to uniport mechanism |
| title_full_unstemmed | LAT1 (SLC7A5) catalyzes copper(histidinate) transport switching from antiport to uniport mechanism |
| title_short | LAT1 (SLC7A5) catalyzes copper(histidinate) transport switching from antiport to uniport mechanism |
| title_sort | lat1 slc7a5 catalyzes copper histidinate transport switching from antiport to uniport mechanism |
| topic | Chemistry Inorganic chemistry Molecular inorganic chemistry Biochemistry |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223018151 |
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