BioAcyl Corp
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Schmiege, P., Donnelly, L., & Elghobashi-Meinhardt, N. (2024). Structure and inhibition of the human lysosomal transporter Sialin. Nature Communications, 15(1), 4386. Added by: Dr. Enrique Feoli (18/02/2026, 16:28) Last edited by: Dr. Enrique Feoli (18/02/2026, 16:29) |
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| Resource type: Journal Article DOI: 10.1038/s41467-024-48535-3 ID no. (ISBN etc.): 2041-1723 BibTeX citation key: Schmiege2024 View all bibliographic details  |
Categories: BioAcyl Corp Subcategories: Entero-salivary cycle Creators: Donnelly, Elghobashi-Meinhardt, Schmiege Collection: Nature Communications |
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| Abstract |
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Sialin, a member of the solute carrier 17 (SLC17) transporter family, is unique in its ability to transport not only sialic acid using a pH-driven mechanism, but also transport mono and diacidic neurotransmitters, such as glutamate and N-acetylaspartylglutamate (NAAG), into synaptic vesicles via a membrane potential-driven mechanism. While most transporters utilize one of these mechanisms, the structural basis of how Sialin transports substrates using both remains unclear. Here, we present the cryogenic electron-microscopy structures of human Sialin: apo cytosol-open, apo lumen-open, NAAG–bound, and inhibitor–bound. Our structures show that a positively charged cytosol-open vestibule accommodates either NAAG or the Sialin inhibitor Fmoc-Leu-OH, while its luminal cavity potentially binds sialic acid. Moreover, functional analyses along with molecular dynamics simulations identify key residues in binding sialic acid and NAAG. Thus, our findings uncover the essential conformational states in NAAG and sialic acid transport, demonstrating a working model of SLC17 transporters.
Added by: Dr. Enrique Feoli Last edited by: Dr. Enrique Feoli |