Cryo-EM reveals mechanism behind transport of a key vascular regulator

The molecule sphingosine-1-phosphate is vital in blood plasma to maintain vascular integrity, immune cell trafficking and support platelet functions. To reach the bloodstream, the transporter protein MFSD2B is necessary to move sphingosine-1-phosphate produced in red blood cells and platelets into the surrounding plasma. However, how this transporter performs its function was unknown. Published in Nature Communications, researchers at St. Jude revealed the structure of MFSD2B using cryo-electron microscopy (cryo-EM). The structure revealed the distinct binding state of sphingosine-1-phosphate deep inside the transporter, anchored by key amino acids. Molecular dynamics simulations and mutagenesis experiments uncovered how sphingosine-1-phosphate gets there and the amino acids that make transport possible. By uncovering the mechanism behind a fundamental process in blood homeostasis, the findings may inform therapeutic efforts to control diseases from autoimmune conditions to cancer.

“MFSD2B has long been recognized as essential, but we lacked a molecular explanation for how it works,” said first author Shahbaz Ahmed, PhD, a scientist in the laboratory of corresponding author Chia-Hsueh Lee, PhD, Department of Structural Biology. “This gives us a much deeper understanding of how red blood cells and platelets contribute to systemic lipid signaling and vascular homeostasis.”

Read more