7MJS

Single-Particle Cryo-EM Structure of Major Facilitator Superfamily Domain containing 2A in complex with LPC-18:3

Summary for 7MJS

• Entry DOI: 10.2210/pdb7mjs/pdb
• EMDB information: 23883
• Descriptor: 2AG3 Fab heavy chain, 2AG3 Fab light chain, Major Facilitator Superfamily Domain containing 2A, ... (5 entities in total)
• Functional Keywords: mfs transporters, lysolipids, blood-brain barrier, omega-3 fatty acids, lipid transport-immune system complex, lipid transport/immune system
• Biological source: Synthetic construct; More
• Total number of polymer chains: 3
• Total formula weight: 111051.95

Authors

Cater, R.J.,Chua, G.L.,Erramilli, S.K.,Keener, J.E.,Choy, B.C.,Tokarz, P.,Chin, C.F.,Quek, D.Q.Y.,Kloss, B.,Pepe, J.G.,Parisi, G.,Wong, B.H.,Clarke, O.B.,Marty, M.T.,Kossiakoff, A.A.,Khelashvili, G.,Silver, D.L.,Mancia, F. (deposition date: 2021-04-20, release date: 2021-06-16, Last modification date: 2024-11-13)

Primary citation

Cater, R.J.,Chua, G.L.,Erramilli, S.K.,Keener, J.E.,Choy, B.C.,Tokarz, P.,Chin, C.F.,Quek, D.Q.Y.,Kloss, B.,Pepe, J.G.,Parisi, G.,Wong, B.H.,Clarke, O.B.,Marty, M.T.,Kossiakoff, A.A.,Khelashvili, G.,Silver, D.L.,Mancia, F.
Structural basis of omega-3 fatty acid transport across the blood-brain barrier.
Nature, 595:315-319, 2021

PubMed Abstract: Docosahexaenoic acid is an omega-3 fatty acid that is essential for neurological development and function, and it is supplied to the brain and eyes predominantly from dietary sources. This nutrient is transported across the blood-brain and blood-retina barriers in the form of lysophosphatidylcholine by major facilitator superfamily domain containing 2A (MFSD2A) in a Na-dependent manner. Here we present the structure of MFSD2A determined using single-particle cryo-electron microscopy, which reveals twelve transmembrane helices that are separated into two pseudosymmetric domains. The transporter is in an inward-facing conformation and features a large amphipathic cavity that contains the Na-binding site and a bound lysolipid substrate, which we confirmed using native mass spectrometry. Together with our functional analyses and molecular dynamics simulations, this structure reveals details of how MFSD2A interacts with substrates and how Na-dependent conformational changes allow for the release of these substrates into the membrane through a lateral gate. Our work provides insights into the molecular mechanism by which this atypical major facility superfamily transporter mediates the uptake of lysolipids into the brain, and has the potential to aid in the delivery of neurotherapeutic agents.

PubMed: 34135507
DOI: 10.1038/s41586-021-03650-9

Experimental method

ELECTRON MICROSCOPY (3.03 Å)