Working mechanisms of the human omega-3 essential fatty acid transporter

The central nervous system (CNS) requires the uptake of omega-3 essential fatty acids in the form of lysophospholipids for normal development and cognitive function, which is accomplished by the major facilitator superfamily transporter MFSD2A. This transporter is enriched at the blood-brain barrier (BBB), a specialized and selective cellular barrier that controls the exchange of trophic factors with the blood and protects the brain from invading pathogens. In particular, lipid uptake by MFSD2A is essential for maintaining low rates of solute transport across the BBB, through repression of vesicle transport across the endothelium, known as transcytosis. For this reason, MFSD2A has emerged as a potential point for pharmacological intervention to facilitate delivery of therapeutic drugs into the CNS. However, the transport mechanism of MFSD2A remains incompletely understood, and no selective inhibitor of MFSD2A to control BBB permeability has been reported.

MFSD2A plays a second important function in human physiology, as a receptor for the retroviral-derived envelope protein syncytin 2 (SYNC2), and MFSD2A-SYNC2 complexes mediate cell-cell fusion and formation of the mother-fetus interface in the placenta . Interestingly, SYNC2 shares the membrane fusion mechanism with existing human retroviruses such as SARS-CoV-2 and HIV. In fact, SYNC2 is encoded by an ancient viral gene that was integrated into the monkey genome over 40 million years ago. Therefore, humans use a receptor-mediated fusion machinery from an ancient virus for placental development, but their receptor-recognition mechanisms remain unknown.

Scientists present the first structural determination of a human endogenous retroviral protein (SYNC2) in complex with its cellular receptor (MFSD2A), revealing a receptor recognition mechanism that has been preserved for millions of years. In addition, the structure of MFSD2A allows direct mapping of mutations that cause microencephaly and intellectual disability in humans and reveals the transporter at an important and elusive intermediate stage in its transport cycle. A comparison of this conformational state with known structures from mfsd2a vertebrate orthologues reveals a unique molecular mechanism for uptake of omega-3 fatty acids in the brain. This mechanism, termed “rock-and-swing”, allows for the occlusion and translocation of the bulky lipid substrate into the transporter core and likely represents a conserved lipid transport mechanism across all kingdoms of life.

Further structural analysis of the MFSD2A-SYNC2 complex suggests that SYNC2 binding can prevent important conformational changes of MFSD2A. Based on this structural observation, researchers designed a soluble fragment of SYNC2 that completely inhibits lipid transport by MFSD2A. This fragment is a first-in-class molecule with the pharmacological potential to transiently increase BBB transcytosis and facilitate delivery of therapeutic macromolecules (eg, antibodies) to the CNS.

© Nicolas Reyes, Maria Martinez-Moledo

Picture: Representative 2D classes and refined 3D cryo-EM map of the 1:1 MFSD2A:SYNC2SU complex. Densities corresponding to MFSD2A (orange), SYNC2SU (green), and lipid/detergent molecules (grey), respectively, are indicated.

Learn more :
Structural insights into the lysophospholipid uptake mechanism in the brain and its inhibition by syncytin 2
Maria Martinez-Moledo, Emmanuel Nji & Nicolas Reyes
Nature Structural and Molecular Biology June 16, 2022

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