Monocarboxylate Transporter: Difference between revisions
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== Structural Architecture == | == Structural Architecture == | ||
The structure (PDB: [[ | 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). | * '''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. | * '''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. | ||
Latest revision as of 07:08, 1 July 2026
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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 and Monocarboxylate transporter 2 promote transport of lactate and pyruvate which are essential for cell metabolism[1],[2] .
- Monocarboxylate transporter 8 transports thyroid hormone across cell membrane[3].
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.
3D sructures of monocarboxylate transporter
Monocarboxylate transporter 3D structures
References
- ↑ Li M, Long X, Wan H, Yin M, Yang B, Zhang F, Guo X. Monocarboxylate transporter 1 promotes proliferation and invasion of renal cancer cells by mediating acetate transport. Cell Biol Int. 2021 Jun;45(6):1278-1287. doi: 10.1002/cbin.11571. Epub 2021 Feb , 19. PMID:33559958 doi:https://dx.doi.org/10.1002/cbin.11571
- ↑ Lin RY, Vera JC, Chaganti RS, Golde DW. Human monocarboxylate transporter 2 (MCT2) is a high affinity pyruvate transporter. J Biol Chem. 1998 Oct 30;273(44):28959-65. PMID:9786900 doi:10.1074/jbc.273.44.28959
- ↑ Friesema EC, Ganguly S, Abdalla A, Manning Fox JE, Halestrap AP, Visser TJ. Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. J Biol Chem. 2003 Oct 10;278(41):40128-35. doi: 10.1074/jbc.M300909200. Epub 2003 , Jul 18. PMID:12871948 doi:https://dx.doi.org/10.1074/jbc.M300909200
- Bågenholm et al. Cryo-EM structure of the human monocarboxylate transporter 10. Structure, 2025. DOI: 10.1016/j.str.2025.02.012
BI3323-Aug2025
