Cryo-EM structure of the human Asc-1 transporter complex

Yaning Li, Yingying Guo, Angelika Bröer, Lu Dai, Stefan Brӧer () and Renhong Yan ()
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Yaning Li: Southern University of Science and Technology
Yingying Guo: Southern University of Science and Technology
Angelika Bröer: Australian National University
Lu Dai: Southern University of Science and Technology
Stefan Brӧer: Australian National University
Renhong Yan: Southern University of Science and Technology

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: 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-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.

Date: 2024
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DOI: 10.1038/s41467-024-47468-1

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