Monocarboxylate Transporter

spinqualitylabelsall models Overall structure of MCT10 (PDB code 9hhq) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D

Introduction

The Human Monocarboxylate Transporter 10 (MCT10), also known as TAT1, is a critical membrane protein encoded by the SLC16A10 gene. While most members of the Solute Carrier 16 (SLC16) family transport monocarboxylates like lactate, MCT10 is functionally distinct; it facilitates the passive transport of aromatic amino acids (phenylalanine, tyrosine, tryptophan) and thyroid hormones (T₃ and T₄).

Thyroid hormones are essential for metabolism and neurological development. A recent study by Bågenholm et al. (2025) presents the cryo-electron microscopy (cryo-EM) structure of human MCT10 (PDB ID: 9hhq), providing the first atomic-level view of this specific transporter class.

• Monocarboxylate transporter 1 promotes transport of lactate and pyruvate which are essential for cell metabolism.

Structural Architecture

The structure (PDB: 9HHQ) reveals the canonical Major Facilitator Superfamily (MFS) fold.

• Topology: The protein comprises 12 transmembrane helices (TM1–TM12) arranged into two pseudo-symmetric bundles: the N-terminal bundle (TM1–TM6) and the C-terminal bundle (TM7–TM12).
• Conformation: The transporter was captured in an inward-open state. In this configuration, the central cavity is accessible from the cytoplasm, while the extracellular gate remains closed.
• Oligomerization: Unlike the homologous MCT2, which forms a dimer, MCT10 functions as a monomer.

Specificity and Binding Mechanism

Molecular docking identifies a central substrate-binding pocket located halfway through the membrane. The pocket utilizes a specific chemical environment to recognize its cargo:

• Salt Bridges: The positively charged residue Arg343 (TM8) is critical for function. It is predicted to form a salt bridge with the carboxyl group of the substrate.
• Hydrophobic Cage: Aromatic residues Phe85 and Phe126 create a hydrophobic environment that stabilizes the bulky aromatic rings of thyroid hormones and amino acids.
• Iodine Interaction: Residues Met403 and Met427 provide sulfur interactions favorable for the iodine atoms in T₃.
• Functional Validation: Mutational analysis confirms that substituting Arg343 or Asp396 with alanine results in a near-total loss of transport activity.

Mechanism of Action

MCT10 likely operates via a "rocker-switch" mechanism. Comparison with AlphaFold models suggests that the N- and C-terminal bundles move as rigid bodies to alternatingly expose the binding site. A distinct kink in TM1 (residues Gln88 and Asn89) acts as a sensor, likely triggering the conformational switch upon substrate binding.

References

1. Bågenholm et al. Cryo-EM structure of the human monocarboxylate transporter 10. Structure, 2025. DOI: 10.1016/j.str.2025.02.012

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BI3323-Aug2025

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