Student Posters 51st Lorne Proteins Conference 2026

Understanding the molecular basis of ligand interactions with MFSD2A (#135)

Ariana Ivanic 1 , Margarida Rosa 2 , Satchal Erramilli 3 , Anthony A. Kossiakoff 3 , George Khelasvhili 2 , Rosemary J. Cater 1
  1. Centre for Chemistry and Drug Discovery, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
  2. Department of Physiology and Biophysics , Weill Cornell Medical College, New York, USA
  3. Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, USA

MFSD2A is an integral membrane protein highly expressed in the endothelial cells of the blood-brain barrier (BBB), where it transports essential ω-3 fatty acids, such as docosahexaenoic acid (DHA), into the brain in the form of lysophosphatidylcholine (LPC-DHA)1. In humans, mutations in MFSD2A are associated with severe neurological disorders, including microcephaly, intracranial hemorrhage and cognitive deficits2-4. Interestingly, recent studies indicate that MFSD2A has a broader physiological significance that extends beyond its ω-3 fatty acid transporter role. This project is focused on uncovering these diverse roles of MFSD2A by biochemically and structurally investigating its interactions with various putative ligands.

Aim 1 will investigate how lithium inhibits MFSD2A-mediated LPC-DHA transport1,5. Given that lithium is widely used as a treatment for bipolar disorder6, elucidating its effects on transporters such as MFSD2A could reveal new insights into how lithium influences brain lipid homeostasis. We have expressed and purified MFSD2A in lithium-containing buffer, confirmed Fab complex formation, and obtained initial cryo-EM 2D class averages of the Fab-bound transporter.

Aim 2 will focus on elucidating the molecular mechanism underlying MFSD2A-mediated transport of the antibiotic tunicamycin, which has been suggested to be an MFSD2A substrate7. Thus far, we have demonstrated in-house that tunicamycin binds to MFSD2A. Elucidation of this transport mechanism will help us understand the substrate promiscuity of MFSD2A and may pave the way for the design of molecules that can hijack the transporter to cross the BBB.

Aim 3 will structurally characterise the interaction between MFSD2A and the Zika virus envelope (ZIKV E) protein, which exploits MFSD2A as a receptor at the blood-brain barrier8. This aim will reveal how viral binding alters MFSD2A function and contributes to BBB disruption during Zika virus infection.

  1. Nguyen, L. N., Ma, D., Shui, G., Wong, P., Cazenave-Gassiot, A., Zhang, X., ... & Silver, D. L. (2014). Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature, 509(7501), 503-506.
  2. Scala, M., Chua, G. L., Chin, C. F., Alsaif, H. S., Borovikov, A., Riazuddin, S., ... & Silver, D. L. (2020). Biallelic MFSD2A variants associated with congenital microcephaly, developmental delay, and recognizable neuroimaging features. European Journal of Human Genetics, 28(11), 1509-1519.
  3. Yang, Y. R., Xiong, X. Y., Liu, J., Wu, L. R., Zhong, Q., Zhou, K., ... & Yang, Q. W. (2017). Mfsd2a (Major facilitator superfamily domain containing 2a) attenuates intracerebral hemorrhage–induced blood–brain barrier disruption by inhibiting vesicular transcytosis. Journal of the American Heart Association, 6(7), e005811.
  4. Qu, C., Song, H., Shen, J., Xu, L., Li, Y., Qu, C., ... & Zhang, J. (2020). Mfsd2a reverses spatial learning and memory impairment caused by chronic cerebral hypoperfusion via protection of the blood–brain barrier. Frontiers in Neuroscience, 14, 461.
  5. Cater, R. J., Chua, G. L., Erramilli, S. K., Keener, J. E., Choy, B. C., Tokarz, P., ... & Mancia, F. (2021). Structural basis of omega-3 fatty acid transport across the blood–brain barrier. Nature, 595(7866), 315-319.
  6. Alda, M. (2015). Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Molecular psychiatry, 20(6), 661-670.
  7. Reiling, J. H., Clish, C. B., Carette, J. E., Varadarajan, M., Brummelkamp, T. R., & Sabatini, D. M. (2011). A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter as a key mediator in the response to tunicamycin. Proceedings of the National Academy of Sciences, 108(29), 11756-11765.
  8. Zhou, J., Chi, X., Cheng, M., Huang, X., Liu, X., Fan, J., ... & Yang, W. (2019). Zika virus degrades the ω-3 fatty acid transporter Mfsd2a in brain microvascular endothelial cells and impairs lipid homeostasis. Science Advances, 5(10), eaax7142.