The SLC13 family of proteins imports various di- and tricarboxylates across the plasma membrane into the human cell. In addition to their nutritional role as TCA cycle intermediates, these carboxylates often function as signaling molecules to regulate cell fate, providing a connection between cellular metabolism and signaling processes. The proteins are implicated in several diseases. Our team has characterized the molecular mechanism of two members of the family, the high affinity sodium-dicarboxylate cotransporter (NaDC3/SLC13A3) and the sodium-citrate cotransporter (NaCT/SLC13A5). Using cryo-EM, we have determined their structures in multiple conformations, including the outward-facing Co, the outward occluded Coo and the inward-facing Ci. In addition to quantitatively describing the elevator-type conformational changes needed for the substrate translocation, these structures also reveal intriguing features, such as an aromatic residue at the scaffold-transport domain interface that helps to control the conformational transition and a water molecule in the middle of the transport domain that functions to stabilize the domain during the transition. Inhibitor-bound structures of the proteins illustrate how these transporters can be inhibited. Combining cryo-EM with biochemical assays, single molecule FRET and molecular dynamics simulations, we aim to understand the complete reaction cycle of these SLC13 proteins, which may lead to therapeutic development.
Wang et al. (Sun,) studied this question.
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