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Interaction of Cholesterol With the Human SLC1A5 (ASCT2): Insights Into Structure/Function Relationships
Mariafrancesca Scalise1, Lorena Pochini1, Jessica Cosco1
1Unit of Biochemistry and Molecular Biotechnology, Department DiBEST (Biologia, Ecologia, Scienze della Terra), University of Calabria, Cosenza, Italy.
Frontiers in Molecular Biosciences
|November 12, 2019
Summary
Cholesterol significantly enhances the transport activity of the ASCT2 amino acid transporter by increasing its maximum transport rate. This interaction involves direct binding of cholesterol to the ASCT2 protein.
Area of Science:
- Biochemistry
- Molecular Biology
- Membrane Transport
Background:
- The human ASCT2 transporter is crucial for amino acid transport and is overexpressed in cancers.
- Understanding ASCT2 regulation is vital for human health and cancer research.
- Cholesterol's role as a modulator of ASCT2 function is under investigation.
Purpose of the Study:
- To investigate the effect of cholesterol on ASCT2 transport activity.
- To determine the mechanism by which cholesterol modulates ASCT2 function.
- To identify potential cholesterol binding sites on the ASCT2 protein.
Main Methods:
- Computational docking of cholesterol into the ASCT2 trimer.
- Experimental evaluation of ASCT2 transport in proteoliposomes using cholesteryl hemisuccinate.
- Chemical modification of tryptophan and cysteine residues to assess cholesterol binding.
Main Results:
- Cholesteryl hemisuccinate strongly stimulated ASCT2 transport activity in proteoliposomes.
- Cholesterol increased the Vmax of ASCT2 transport approximately threefold without altering Km.
- Docking analysis predicted cholesterol binding sites, including near CARC/CRAC motifs, and experimental data confirmed direct cholesterol-protein interaction.
Conclusions:
- Cholesterol directly interacts with the ASCT2 transporter.
- Cholesterol binding enhances ASCT2 transport activity by modulating its Vmax.
- These findings provide insights into the regulation of amino acid transport by lipids.
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