Mechanisms of action of 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 achieved by the major transporter of the MFSD2A superfamily. This transporter is enriched at the blood-brain barrier (BBB), a specialized and selective cellular barrier that controls the exchange of nutritional factors with the blood and protects the brain from pathogen invasion. In particular, lipid uptake by MFSD2A is essential for maintaining low rates of solute transport across the BBB, by suppressing vesicle trafficking through the endothelium, known as transcytosis. For this reason, MFSD2A has emerged as a potential point of pharmacological intervention to facilitate delivery of therapeutic drugs to the central nervous system. However, the transport mechanism of MFSD2A is still not fully understood, and no selective inhibitor of MFSD2A has been reported to control BBB permeability.

MFSD2A plays a second important function in human physiology, as a receptor for the retroviral-derived envelope protein SYNC2 (SYNC2), and MFSD2A-SYNC2 complexes mediate cell-cell fusion and formation of the maternal-fetal interface at the placenta. Interestingly, SYNC2 shares a membrane fusion mechanism with extant 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 more than 40 million years ago. Therefore, humans use receptor-mediated fusion machines from an ancient virus to develop the placenta, but the mechanisms for recognition of its receptors remain unknown.

Scientists have provided the first structural identification of a human retroviral protein (SYNC2) in complex with its cellular receptor (MFSD2A), revealing a receptor recognition mechanism that has been conserved for millions of years. Moreover, the structure of MFSD2A allows direct mapping of mutations that cause microencephaly and intellectual disabilities in humans, and the carrier appears in an important and elusive intermediate state of its transport cycle. Comparison of this case-matched with the reported structures of vertebrate orthologs mfsd2a reveals a unique molecular mechanism of omega-3 fatty acid uptake in the brain. This mechanism, called ‘rock and swing’, allows the bulky lipid substrate to be blocked and transported to the carrier core, and likely represents a conserved lipid transport mechanism across all kingdoms of life.

Additional structural analysis of the MFSD2A-SYNC2 complex indicates that SYNC2 binding may prevent important conformational changes of MFSD2A. Based on this structural observation, the researchers developed a soluble fragment of SYNC2 that completely inhibits lipid transport by MFSD2A. This fraction constitutes the first molecule of its class with the pharmacological ability to transiently increase intracellular translocation of the BBB and facilitate the delivery of large therapeutic molecules (eg, antibodies) to the CNS.

© Nicholas Reyes, Maria Martinez Moledo

picture: Representative 2D classes and a refined 3D cryo-EM map of the MFSD2A 1:1 complex: SYNC2SU. The corresponding densities of MFSD2A (orange), SYNC2SU (green) and lipid/detergent (gray) molecules are indicated.

To find out more:
Structural insights into the mechanism of brain uptake and inhibition of lysophospholipids by synestin 2 .
Maria Martinez Moledo, Emmanuel Njie and Nicholas Reyes
Structural and Molecular Biology Nature June 16, 2022 https://doi.org/10.1038 / s41594-022-00786-8

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