LAT1 (SLC7A5) catalyzes copper(histidinate) transport switching from antiport to uniport mechanism
Raffaella Scanga,
Mariafrancesca Scalise,
Nadia Marino,
Francesco Parisi,
Donatella Barca,
Michele Galluccio,
Chiara Brunocilla,
Lara Console,
Cesare Indiveri
Affiliations
Raffaella Scanga
Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, 87036 Arcavacata di Rende, Italy
Mariafrancesca Scalise
Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, 87036 Arcavacata di Rende, Italy
Nadia Marino
MAT-INLAB (Laboratorio di Materiali Molecolari Inorganici), Department of Chemistry and Chemical Technologies (CTC), University of Calabria—UNICAL, Via P. Bucci, 87036 Arcavacata di Rende, Italy
Francesco Parisi
MAT-INLAB (Laboratorio di Materiali Molecolari Inorganici), Department of Chemistry and Chemical Technologies (CTC), University of Calabria—UNICAL, Via P. Bucci, 87036 Arcavacata di Rende, Italy
Donatella Barca
Department DiBEST (Biologia, Ecologia e Scienze della Terra), 87036 Arcavacata di Rende, Italy
Michele Galluccio
Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, 87036 Arcavacata di Rende, Italy
Chiara Brunocilla
Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, 87036 Arcavacata di Rende, Italy
Lara Console
Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, 87036 Arcavacata di Rende, Italy
Cesare Indiveri
Department 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 author
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.