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. 2021 Dec 8;12:7147. doi: 10.1038/s41467-021-27414-1

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — a System xc⁻ consists of a heavy chain component, 4F2hc (SLC3A2) and a transport module, xCT (SLC7A11), and functions as a dedicated cystine import system, exchanging extracellular l-cystine for intracellular l-glutamate. Following l-cystine transport into the cell, the molecule is rapidly reduced to l-cysteine via cystine reductase and used to regulate cellular redox levels via glutathione, alternatively free cysteine can also enter the protein synthesis pathway. b Cryo-EM density of 4F2hc (magenta) and xCT (blue) contoured at a threshold level of 1.0, superposed with lower-contoured threshold level of 0.22 to display the detergent micelle (grey). c Cartoon representation of system xc⁻, with 4F2hc (grey) showing conserved N-linked glycans (NAG). xCT is coloured blue from the N-termini to red at the C-terminus. The cysteines forming the disulphide which connects the two components are also indicated. A topology diagram is also shown of SLC7A11, using the same colours as in the main panel. d Analysis of the interactions between 4F2hc and xCT. The zoomed in views show the interactions between the extracellular domain (green box) and transmembrane domains (orange box).