@article {68771, title = {Lipid flipping in the omega-3 fatty-acid transporter.}, journal = {Nature Communications}, volume = {14}, year = {2023}, month = {2023 May 08}, pages = {2571}, abstract = {

Mfsd2a is the transporter for docosahexaenoic acid (DHA), an omega-3 fatty acid, across the blood brain barrier (BBB). Defects in Mfsd2a are linked to ailments from behavioral and motor dysfunctions to microcephaly. Mfsd2a transports long-chain unsaturated fatty-acids, including DHA and α-linolenic acid (ALA), that are attached to the zwitterionic lysophosphatidylcholine (LPC) headgroup. Even with the recently determined structures of Mfsd2a, the molecular details of how this transporter performs the energetically unfavorable task of translocating and flipping lysolipids across the lipid bilayer remains unclear. Here, we report five single-particle cryo-EM structures of Danio rerio Mfsd2a (drMfsd2a): in the inward-open conformation in the ligand-free state and displaying lipid-like densities modeled as ALA-LPC at four distinct\ positions. These Mfsd2a snapshots detail the flipping mechanism for lipid-LPC from outer to inner membrane leaflet and release for membrane integration on the cytoplasmic side. These results also map Mfsd2a mutants that disrupt lipid-LPC transport and are associated with disease.

}, keywords = {Biological Transport, Blood-Brain Barrier, Docosahexaenoic Acids, Fatty Acids, Omega-3, Lysophosphatidylcholines, Membrane Transport Proteins, Symporters}, issn = {2041-1723}, doi = {10.1038/s41467-023-37702-7}, author = {Nguyen, Chi and Lei, Hsiang-Ting and Lai, Louis Tung Faat and Gallenito, Marc J and Mu, Xuelang and Matthies, Doreen and Gonen, Tamir} } @article {56203, title = {Structural basis for substrate binding and specificity of a sodium-alanine symporter AgcS.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {116}, year = {2019}, month = {2019 Jan 18}, pages = {2086-90}, abstract = {

The amino acid, polyamine, and organocation (APC) superfamily is the second largest superfamily of membrane proteins forming secondary transporters that move a range of organic molecules across the cell membrane. Each transporter in the APC superfamily is specific for a unique subset of substrates, even if they possess a similar structural fold. The mechanism of substrate selectivity remains, by and large, elusive. Here, we report two crystal structures of an APC member from , the alanine or glycine:cation symporter (AgcS), with l- or d-alanine bound. Structural analysis combined with site-directed mutagenesis and functional studies inform on substrate binding, specificity, and modulation of the AgcS family and reveal key structural features that allow this transporter to accommodate glycine and alanine while excluding all other amino acids. Mutation of key residues in the substrate binding site expand the selectivity to include valine and leucine. These studies provide initial insights into substrate selectivity in AgcS symporters.

}, issn = {1091-6490}, doi = {10.1073/pnas.1806206116}, author = {Ma, Jinming and Lei, Hsiang-Ting and Reyes, Francis E and Sanchez-Martinez, Silvia and Sarhan, Maen F and Hattne, Johan and Gonen, Tamir} } @article {49264, title = {Crystal structure of arginine-bound lysosomal transporter SLC38A9 in the cytosol-open state.}, journal = {Nature Structural \& Molecular Biology}, volume = {25}, year = {2018}, month = {2018 Jun}, pages = {522-527}, abstract = {

Recent advances in understanding intracellular amino acid transport and mechanistic target of rapamycin complex 1 (mTORC1) signaling shed light on solute carrier 38, family A member 9 (SLC38A9), a lysosomal transporter responsible for the binding and translocation of several essential amino acids. Here we present the first crystal structure of SLC38A9 from Danio rerio in complex with arginine. As captured in the cytosol-open state, the bound arginine was locked in a transitional state stabilized by transmembrane helix 1 (TM1) of drSLC38A9, which was anchored at the groove between TM5 and TM7. These anchoring interactions were mediated by the highly conserved WNTMM motif in TM1, and mutations in this motif abolished arginine transport by drSLC38A9. The underlying mechanism of substrate binding is critical for sensitizing the mTORC1 signaling pathway to amino acids and for maintenance of lysosomal amino acid homeostasis. This study offers a first glimpse into a prototypical model for SLC38 transporters.

}, issn = {1545-9985}, doi = {10.1038/s41594-018-0072-2}, author = {Lei, Hsiang-Ting and Ma, Jinming and Sanchez Martinez, Silvia and Gonen, Tamir} }