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

Li, Yaning1,2,3; Guo, Yingying1; Broer, Angelika4; Dai, Lu1; Bror, Stefan4; Yan, Renhong1

2024-04-08

10.1038/s41467-024-47468-1

NATURE COMMUNICATIONS   影响因子和分区

2041-1723

["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 angstrom, 3.5 angstrom, and 3.4 angstrom, 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.","The human Asc-1-4F2hc complex plays an important role in the neural development and stability. Here, authors determine the cryo-EM structures of Asc-1-4F2hc complex in three states, revealing its substrate recognition and transport mechanism."]

SCI

英语

第一 ; 通讯

This work was funded by the National Natural Science Foundation of China (82202517 to R.Y.) and the Major Talent Recruitment Program of Guangdong Province (2021QNO2Y167 to R.Y.).[82202517] ; Cryo-EM Facility of Southern University of Science and Technology (SUSTech) - National Natural Science Foundation of China[2021QNO2Y167]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:001198902100021

NATURE PORTFOLIO

Web of Science

1.Key Univ Lab Metab & Hlth Guangdong, Southern Univ Sci & Technol, Sch Med, Dept Biochem, Shenzhen, Guangdong, Peoples R China
2.Southern Univ Sci & Technol, Inst Biol Electron Microscopy, Shenzhen, Guangdong, Peoples R China
3.Tsinghua Univ, Beijing Adv Innovat Ctr Struct Biol, Tsinghua Peking Joint Ctr Life Sci, Sch Life Sci, Beijing 100084, Peoples R China
4.Australian Natl Univ, Res Sch Biol, Canberra, ACT, Australia

Li, Yaning,Guo, Yingying,Broer, Angelika,et al. Cryo-EM structure of the human Asc-1 transporter complex[J]. NATURE COMMUNICATIONS,2024,15(1).

Li, Yaning,Guo, Yingying,Broer, Angelika,Dai, Lu,Bror, Stefan,&Yan, Renhong.(2024).Cryo-EM structure of the human Asc-1 transporter complex.NATURE COMMUNICATIONS,15(1).

Li, Yaning,et al."Cryo-EM structure of the human Asc-1 transporter complex".NATURE COMMUNICATIONS 15.1(2024).