MFSD2A Membrane Protein Introduction

Introduction of MFSD2A

MFSD2A is a sodium-dependent lysophosphatidylcholine (LPC) symporter which is mainly expressed at the blood-brain barrier. MFSD2A transports LPC including DHA and other long-chain fatty acids. The three-dimensional structural model of MFSD2A shows that it has 12 transmembrane helices and connecting loops. In addition to its binding site to sodium, it has three unique structural features: phosphate head binding sites, hydrophobic cracks to accommodate hydrophobic hydrocarbon tails, and three sets of ion locks that stabilize the outward open conformation. Lys436 is a key residue for transport, forming a negatively charged salt bridge on the phosphate head group. LPCs are “flipped” within the transporter cavity by pivoting about Lys436 leading to net transport from the outer to the inner leaflet of the plasma membrane.

Function of MFSD2A Membrane Protein

MFSD2A is the primary pathway for the import of docosahexaenoic acid and other long-chain fatty acids into the brains of fetuses and adults, and is important for the growth and function of the brains in mice and humans. MFSD2A is the first member of the MFS transport lipid family, indicating that MFSD2A has unique structural features and transport mechanisms. In addition, the MFSD2A-associated LPC transport pathway has been shown to be essential for human brain development. MFSD2A is highly expressed in RPE in the embryonic eye before photoreceptor development, and the eye is the main site of MFSD2A expression. Eyes of MFSD2A deficient (KO) mice but not endothelial-specific MFSD2A deficient mice are DHA deficient and have significantly reduced LPC-DHA transport in vivo.

Fig.1 The overall structure of the MFSD2A. (Quek, 2016)

Application of MFSD2A Membrane Protein in Literature

1. Wong B.H., et al. Mfsd2a Is a Transporter for the Essential ω-3 Fatty Acid Docosahexaenoic Acid (DHA) in Eye and Is Important for Photoreceptor Cell Development. Journal of Biological Chemistry. 2016, 291(20): 10501-14. PubMed ID: 27008858
   
   

   This article identifies that MFSD2A is an essential subunit of VRAC and a key factor for astroglial volume homeostasis.

2. Tiwary S., et al. Metastatic Brain Tumors Disrupt the Blood-Brain Barrier and Alter Lipid Metabolism by Inhibiting Expression of the Endothelial Cell Fatty Acid Transporter Mfsd2a. Scientific Reports. 2018, 8(1): 8267. PubMed ID: 29844613
   
   

   This paper reveals the basic pathways by which metastatic cancer cells destroy BBB and shows that restoring DHA metabolism in the brain tumor microenvironment may be a novel therapeutic strategy to block the growth and survival of metastatic cells.

3. Ungaro F., et al. MFSD2A Promotes Endothelial Generation of Inflammation-resolving Lipid Mediators and Reduces Colitis in Mic. Gastroenterology. 2017, 153(5): 1363-1377. PubMed ID: 28827082
   
   

   This article reveals that over-expressed MFSD2A in endothelial progenitor cells can alleviate colitis in mice, and intestinal inflammation in patients with colitis may be resolved by inducing this pathway.

4. Yang Y.R., et al. 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 Cardiovascular & Cerebrovascular Disease. 2017, 6(7): e005811. PubMed ID: 28724654
   
   

   This review suggests that Mfsd2a may prevent BBB injury by inhibiting vesicular transcytosis after ICH.

5. Moritake H., et al. A mouse model reveals that Mfsd2a is critical for unfolded protein response upon exposure to tunicamycin. Human Cell. 2017, 30(2): 88-97. PubMed ID: 27885588
   
   

   This article shows significant attenuation of TM DDIT3 induction in both liver and brain of Mfsd2a deficient mice and indicates that Mfsd2a plays a key role in UPR upon TM exposure.

MFSD2A Preparation Options

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Reference

1. Quek D.Q.Y., et al. (2016). Structural Insights into the Transport Mechanism of the Human Sodium-dependent Lysophosphatidylcholine Transporter MFSD2A. Journal of Biological Chemistry. 291(18): 9383-9394.

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