Structure and inhibition of the human lysosomal transporter Sialin

Philip Schmiege, Linda Donnelly, Nadia Elghobashi-Meinhardt, Chia-Hsueh Lee and Xiaochun Li ()
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Philip Schmiege: University of Texas Southwestern Medical Center
Linda Donnelly: University of Texas Southwestern Medical Center
Nadia Elghobashi-Meinhardt: University College Dublin
Chia-Hsueh Lee: St. Jude Children’s Research Hospital
Xiaochun Li: University of Texas Southwestern Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-48535-3

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