Docosahexaenoic acid (DHA) is an ω-3 fatty acid found at incredibly high concentrations within the brain and is essential for normal brain functioning and development. Despite this, the brain cannot synthesize DHA de novo and we rely heavily on systemic and dietary sources of DHA to be transported across the blood-brain barrier (BBB) as a means of supply. It was recently demonstrated that a member of the Major Facilitator Superfamily (MFS) of transporters - MFSD2A - is highly expressed by endothelial cells of the BBB and is the primary route via which the brain acquires DHA. As well as serving a vital physiological function, LPC-DHA transport via MFSD2A is biophysically and evolutionarily curious given that the majority of transporters from the MFS mediate transport of small, water-soluble molecules.
MFSD2A has a molecular weight of 58 kDa and is only able to transport DHA that is chemically complexed with lysophosphatidylcholine (LPC-DHA). Here I have used single particle cryogenic electron microscopy (cryo-EM) to obtain a 3.6 Å resolution structure of apo-MFSD2A reconstituted in nanodisc and complexed with two FABs (50 kDa each) to introduce soluble features for cryo-EM purposes. This structure provides our first insight as to how MFSD2A transports DHA across the BBB and will provide insight into how MFS transporters can transport lipid molecules across cell membranes. Furthermore, this research has the potential to lay the foundation for the rational design of neurotherapeutics that “hijack” MFSD2A for delivery across the blood brain barrier, which is a major bottleneck in neurotherapeutic development.