2023/07/26 by Haiping Tang, Huanyu Li, Dheeraj Prakaash +6 · 1 voice · 2 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Erythrocyte Function and Pathophysiology #Lipid Membrane Structure and Behavior #Sphingolipid Metabolism and Signaling
paper · pdf · doi:10.1016/j.molcel.2023.06.033
openalex publication_date 2023/07/26 · openalex created_date 2023/07/27 · openalex updated_date 2026/07/28
Solute carrier spinster homolog 2 (SPNS2), one of only four known major facilitator superfamily (MFS) lysolipid transporters in humans, exports sphingosine-1-phosphate (S1P) across cell membranes. Here, we explore the synergistic effects of lipid binding and conformational dynamics on SPNS2's transport mechanism. Using mass spectrometry, we discovered that SPNS2 interacts preferentially with PI(4,5)P 2 . Together with functional studies and molecular dynamics (MD) simulations, we identified potential PI(4,5)P 2 binding sites. Mutagenesis of proposed lipid binding sites and inhibition of PI(4,5)P 2 synthesis reduce S1P transport, whereas the absence of the N terminus renders the transporter essentially inactive. Probing the conformational dynamics of SPNS2, we show how synergistic binding of PI(4,5)P 2 and S1P facilitates transport, increases dynamics of the extracellular gate, and stabilizes the intracellular gate. Given that SPNS2 transports a key signaling lipid, our results have implications for therapeutic targeting and also illustrate a regulatory mechanism for MFS transporters.