The monocarboxylate transporter family--Structure and functional characterization

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Monocarboxylate transporters (MCTs) are crucial for transporting monocarboxylates, including lactate and ketone bodies, across cell membranes.
• The SLC16 family, or MCT family, comprises 14 members, including isoforms MCTs 1-4 responsible for proton-linked monocarboxylate transport.
• This family also includes specialized transporters like MCT8 (thyroid hormone) and MCT10 (aromatic amino acids), alongside uncharacterized members.

Purpose of the Study:

• To elucidate the structural and functional characteristics of monocarboxylate transporters (MCTs).
• To investigate the role of ancillary proteins in the plasma membrane localization and activity of MCTs.
• To understand the mechanism of substrate translocation and inhibitor binding in MCTs.

Main Methods:

• Utilized labeling studies and proteolytic digestion to confirm predicted transmembrane topology of MCTs.
• Employed site-directed mutagenesis to identify key residues for catalysis and inhibitor binding.
• Developed molecular models of MCT1 to propose a translocation cycle mechanism.

Main Results:

• Confirmed the predicted 12 transmembrane helices and intracellular termini for MCTs.
• Identified critical residues for MCT function and developed a molecular model for MCT1 translocation.
• Demonstrated that MCTs 1-4 require association with glycosylated ancillary proteins (basigin or embigin) for plasma membrane targeting and activity.

Conclusions:

• MCTs possess a conserved structure with key residues mediating transport.
• Ancillary proteins are essential for the correct localization and function of specific MCT isoforms at the plasma membrane.
• While ancillary proteins do not alter substrate specificity, they can influence inhibitor binding profiles for MCTs.