Abstract
In human and other mammalian cells, transport of L-lactate across plasma membranes is mainly catalyzed by monocarboxylate transporters (MCTs) of the SLC16 solute carrier family. MCTs play an important role in cancer metabolism and are promising targets for tumor treatment. Here, we report the crystal structures of an SLC16 family homologue with two different bound ligands at 2.54 and 2.69 Å resolution. The structures show the transporter in the pharmacologically relevant outward-open conformation. Structural information together with a detailed structure-based analysis of the transport function provide important insights into the molecular working mechanisms of ligand binding and L-lactate transport.
Highlights
In human and other mammalian cells, transport of L-lactate across plasma membranes is mainly catalyzed by monocarboxylate transporters (MCTs) of the SLC16 solute carrier family
MCTs are predicted to adopt a protein fold that is characteristic for members of the major facilitator superfamily (MFS), which contain 12 transmembrane helices (TMs) arranged in two six-helix bundles
We have identified a transporter from Syntrophobacter fumaroxidans (SfMCT) that shares 25 and 27% amino acid sequence identity, and 51 and 57% sequence similarity with the human SLC16 family L-lactate transporters MCT1 and MCT4
Summary
Among the tested linear unsubstituted monocarboxylates, only propionate and butyrate significantly reduced [14C]L-lactate uptake (Fig. 1b) without being transported (Supplementary Fig. 1b). This indicates that besides a carboxylate group, an aliphatic chain consisting of at least three carbon atoms is required for significant competition. The carboxylate group of TSA interacts with the hydroxyl group of Y119 (TM4) and the Nη nitrogen atoms of the guanidinium group of R280 (TM8) (Fig. 3b, c) This positively charged residue is conserved in TM8 of most SLC16 family members[3,4].
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