Structure and inhibition of the human lysosomal transporter Sialin.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
23 May 2024
23 May 2024
Historique:
received:
29
11
2023
accepted:
03
05
2024
medline:
24
5
2024
pubmed:
24
5
2024
entrez:
23
5
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38782953
doi: 10.1038/s41467-024-48535-3
pii: 10.1038/s41467-024-48535-3
doi:
Substances chimiques
sialic acid transport proteins
0
N-Acetylneuraminic Acid
GZP2782OP0
Organic Anion Transporters
0
Dipeptides
0
Symporters
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4386Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : R35GM149533
Organisme : U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
ID : P01HL160487
Organisme : G. Harold and Leila Y. Mathers Foundation (G. Harold & Leila Y. Mathers Foundation)
ID : MF-2302-03702
Organisme : Welch Foundation
ID : I-1957
Organisme : U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ID : F31HD110229
Informations de copyright
© 2024. The Author(s).
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