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

Authors

Shahbaz Ahmed, Min Huang, Yaxin Dai, Xuebo Yang, Jiajun Dong, Xiang Yu, Chia-Hsueh Lee, Long N Nguyen

Published in

Nature communications. Volume 17. Issue 1. Aug 12, 2026. Epub Aug 12, 2026.

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 Å 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 transporter's 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.

PMID:
42717192
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.

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