Structural basis for pH-responsive amino acid transport via SLC7A4

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Amino acid transport is vital for cellular functions like metabolism and signaling.
• The amino acid polyamine organocation (APC) superfamily mediates amino acid transport through various mechanisms.
• Mechanisms of pH-regulated amino acid transport in mammals remain largely unknown.

Purpose of the Study:

• To elucidate the function and pH-regulation of the human plasma membrane amino acid transporter SLC7A4.
• To investigate the structural basis for pH-gated amino acid selectivity within the SLC7 family.

Main Methods:

• Utilized Cryo-electron microscopy (Cryo-EM) structures of a plant homolog (CAT4).
• Performed transport assays and molecular dynamics simulations on homology models of human SLC7A4.
• Identified key residues involved in amino acid selectivity and pH regulation.

Main Results:

• Demonstrated that human SLC7A4 is regulated by low extracellular pH and transports leucine.
• Identified an allosteric mechanism linking ligand binding to pH-dependent transport regulation.
• Established an evolutionary link between mammalian SLC7A4 and proton-coupled prokaryotic transporters.

Conclusions:

• Provided a structural and functional basis for pH-gated leucine transport by human SLC7A4.
• Established a framework for understanding amino acid selectivity in the broader SLC7 transporter family.
• Highlighted the importance of pH regulation in mammalian amino acid transport mechanisms.