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Title | Cryo-EM structure of the human Asc-1 transporter complex. |
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Journal, issue, pages | Nat Commun, Vol. 15, Issue 1, Page 3036, Year 2024 |
Publish date | Apr 8, 2024 |
Authors | Yaning Li / Yingying Guo / Angelika Bröer / Lu Dai / Stefan Brӧer / Renhong Yan / |
PubMed Abstract | 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- ...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 links | Nat Commun / PubMed:38589439 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.42 - 3.5 Å |
Structure data | EMDB-37671, PDB-8wns: EMDB-37672, PDB-8wnt: EMDB-37675, PDB-8wny: |
Chemicals | ChemComp-NAG: ChemComp-ALA: ChemComp-DSN: |
Source |
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Keywords | MEMBRANE PROTEIN / SLC7A10 / SLC3A2 / ASC-1 |