Structural basis of lipid head group entry to the Kennedy pathway by FLVCR1 Journal Article
| Authors: | Son, Y.; Kenny, T. C.; Khan, A.; Birsoy, K.; Hite, R. K. |
| Article Title: | Structural basis of lipid head group entry to the Kennedy pathway by FLVCR1 |
| Abstract: | Phosphatidylcholine and phosphatidylethanolamine, the two most abundant phospholipids in mammalian cells, are synthesized de novo by the Kennedy pathway from choline and ethanolamine, respectively1–6. Despite the essential roles of these lipids, the mechanisms that enable the cellular uptake of choline and ethanolamine remain unknown. Here we show that the protein encoded by FLVCR1, whose mutation leads to the neurodegenerative syndrome posterior column ataxia and retinitis pigmentosa7–9, transports extracellular choline and ethanolamine into cells for phosphorylation by downstream kinases to initiate the Kennedy pathway. Structures of FLVCR1 in the presence of choline and ethanolamine reveal that both metabolites bind to a common binding site comprising aromatic and polar residues. Despite binding to a common site, FLVCR1 interacts in different ways with the larger quaternary amine of choline in and with the primary amine of ethanolamine. Structure-guided mutagenesis identified residues that are crucial for the transport of ethanolamine, but dispensable for choline transport, enabling functional separation of the entry points into the two branches of the Kennedy pathway. Altogether, these studies reveal how FLVCR1 is a high-affinity metabolite transporter that serves as the common origin for phospholipid biosynthesis by two branches of the Kennedy pathway. © The Author(s), under exclusive licence to Springer Nature Limited 2024. |
| Keywords: | protein phosphorylation; carrier protein; unclassified drug; gene mutation; human cell; genetics; mutation; nonhuman; mouse; animal; metabolism; animals; cell viability; gene; carboxy terminal sequence; lipid; animal experiment; protein; genetic variability; phosphorylation; chemistry; amino terminal sequence; escherichia coli; choline; clinical pathway; binding protein; binding site; models, molecular; binding sites; phosphatidylethanolamine; phosphatidylethanolamines; streptococcus pneumoniae; ataxia; metabolite; mutagenesis; biological transport; liposome; molecular model; phosphatidylcholine; complementary dna; separation; phospholipid; retinitis pigmentosa; cryoelectron microscopy; hypothesis; cell; transport at the cellular level; membrane transport proteins; cell receptor; phosphatidylcholines; membrane potential; humans; human; article; clustered regularly interspaced short palindromic repeat; choline uptake; vector control; phospholipid synthesis; sinorhizobium meliloti; ethanolamine; hek293t cell line; root mean squared error; ethanolamine phosphotransferase; feline leukemia virus subgroup c cellular receptor 1; chka gene; flvcr1 gene; kennedy pathway; w125a gene; y153a gene; y349a gene |
| Journal Title: | Nature |
| Volume: | 629 |
| Issue: | 8012 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-05-16 |
| Start Page: | 710 |
| End Page: | 716 |
| Language: | English |
| DOI: | 10.1038/s41586-024-07374-4 |
| PUBMED: | 38693265 |
| PROVIDER: | scopus |
| PMCID: | PMC11188936 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Richard K. Hite -- Source: Scopus |
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