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TitleCryo-EM structure of the human Asc-1 transporter complex.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 3036, Year 2024
Publish dateApr 8, 2024
AuthorsYaning Li / Yingying Guo / Angelika Bröer / Lu Dai / Stefan Brӧer / Renhong Yan /
PubMed AbstractThe Alanine-Serine-Cysteine transporter 1 (Asc-1 or SLC7A10) forms a crucial heterodimeric transporter complex with 4F2hc (SLC3A2) through a covalent disulfide bridge. This complex enables the sodium- ...The Alanine-Serine-Cysteine transporter 1 (Asc-1 or SLC7A10) forms a crucial heterodimeric transporter complex with 4F2hc (SLC3A2) through a covalent disulfide bridge. This complex enables the sodium-independent transport of small neutral amino acids, including L-Alanine (L-Ala), Glycine (Gly), and D-Serine (D-Ser), within the central nervous system (CNS). D-Ser and Gly are two key endogenous glutamate co-agonists that activate N-methyl-d-aspartate (NMDA) receptors by binding to the allosteric site. Mice deficient in Asc-1 display severe symptoms such as tremors, ataxia, and seizures, leading to early postnatal death. Despite its physiological importance, the functional mechanism of the Asc-1-4F2hc complex has remained elusive. Here, we present cryo-electron microscopy (cryo-EM) structures of the human Asc-1-4F2hc complex in its apo state, D-Ser bound state, and L-Ala bound state, resolved at 3.6 Å, 3.5 Å, and 3.4 Å, respectively. Through detailed structural analysis and transport assays, we uncover a comprehensive alternating access mechanism that underlies conformational changes in the complex. In summary, our findings reveal the architecture of the Asc-1 and 4F2hc complex and provide valuable insights into substrate recognition and the functional cycle of this essential transporter complex.
External linksNat Commun / PubMed:38589439 / PubMed Central
MethodsEM (single particle)
Resolution3.42 - 3.5 Å
Structure data

EMDB-37671, PDB-8wns:
Cryo EM map of SLC7A10 in the apo state
Method: EM (single particle) / Resolution: 3.42 Å

EMDB-37672, PDB-8wnt:
Cryo EM map of SLC7A10 with L-Alanine substrate
Method: EM (single particle) / Resolution: 3.42 Å

EMDB-37675, PDB-8wny:
Cryo EM map of SLC7A10-SLC3A2 complex in the D-serine bound state
Method: EM (single particle) / Resolution: 3.5 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-ALA:
ALANINE / Alanine

ChemComp-DSN:
D-SERINE / Serine

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / SLC7A10 / SLC3A2 / ASC-1

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