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TitleStructure and inhibition of the human lysosomal transporter Sialin.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 4386, Year 2024
Publish dateMay 23, 2024
AuthorsPhilip Schmiege / Linda Donnelly / Nadia Elghobashi-Meinhardt / Chia-Hsueh Lee / Xiaochun Li /
PubMed AbstractSialin, 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 ...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.
External linksNat Commun / PubMed:38782953 / PubMed Central
MethodsEM (single particle)
Resolution2.83 - 3.67 Å
Structure data

EMDB-41858, PDB-8u3d:
Structure of Apo Sialin at pH7.5
Method: EM (single particle) / Resolution: 2.83 Å

EMDB-41859, PDB-8u3e:
Structure of Apo Sialin at pH5.0
Method: EM (single particle) / Resolution: 3.19 Å

EMDB-41860, PDB-8u3f:
Structure of Apo Sialin R168K mutant
Method: EM (single particle) / Resolution: 3.31 Å

EMDB-41861, PDB-8u3g:
Structure of NAAG-bound Sialin
Method: EM (single particle) / Resolution: 3.42 Å

EMDB-41862, PDB-8u3h:
Structure of Fmoc-Leu-OH bound Sialin
Method: EM (single particle) / Resolution: 3.67 Å

EMDB-43984, PDB-9ayb:
Structure of Apo Sialin S61A mutant
Method: EM (single particle) / Resolution: 3.19 Å

Chemicals

ChemComp-ACE:
ACETYL GROUP

ChemComp-ASP:
ASPARTIC ACID

ChemComp-GLU:
GLUTAMIC ACID


ChemComp, No image

ChemComp-VP1:
Unknown entry

ChemComp-LEU:
LEUCINE

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Transporter

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