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bioRxiv · 10.64898/2026.01.16.700024

Structure and mechanism of human sphingosine-1-phosphate transporter MFSD2B

Ahmed, S.·Huang, M.·Dai, Y.·Yang, X.·Lee, C.-H.·Nguyen, L. N.
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Abstract

Sphingosine-1-phosphate (S1P) is an essential signaling lipid that maintains vascular integrity and regulates immune cell trafficking. The major facilitator superfamily domain-containing protein 2B (MFSD2B) serves as the main S1P exporter in red blood cells and platelets; however, its structure and transport mechanism are unclear. Here, we report the 3.0 [A] cryo-EM structure of human MFSD2B bound to S1P. S1P is captured in a distinctive binding state, deeply buried within the C-domain, with its sphingoid tail accommodated by a hydrophobic pocket and its phosphate group coordinated by a cluster of polar residues within the transporters cavity. Mutagenesis and molecular dynamics simulations identify the TM2/TM11 lateral opening as the primary pathway for S1P translocation, with key charged residues acting as sequential anchors during transport. Furthermore, we demonstrate that MFSD2B functions as a uniporter, and that subtle rewiring of local charge networks can alter its coupling mechanism. Our work provides a molecular framework for understanding S1P transport mediated by MFSD2B in hematopoietic cells.

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Ahmed, S., Huang, M., Dai, Y., Yang, X., Lee, C.-H., Nguyen, L. N.. 2026-01-17. Structure and mechanism of human sphingosine-1-phosphate transporter MFSD2B. https://doi.org/10.64898/2026.01.16.700024

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