Structural insights reveal interplay between LAG-3 homodimerization, ligand binding, and function

• 成果类型: Article
• 署名作者: Silberstein, John L.; Du, Jasper; Chan, Kun-Wei; Frank, Jessica A.; Mathews, Irimpan I.; Kim, Yong Bin; You, Jia; Lu, Qiao; Liu, Jia; Philips, Elliot A.; Liu, Phillip; Rao, Eric; Fernandez, Daniel; Rodriguez, Grayson E.; Kong, Xiang-Peng; Wang, Jun; Cochran, Jennifer R.
• 署名单位: Stanford University; Stanford University; New York University; New York University; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory; Stanford University; Stanford University; Stanford University; New York University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15409
• DOI: 10.1073/pnas.2310866121
• 发表日期: 2024-03-19
• 关键词: antibodies; protein; cells; cd223

摘要

Lymphocyte activation gene - 3 (LAG - 3) is an inhibitory receptor expressed on activated T cells and an emerging immunotherapy target. Domain 1 (D1) of LAG - 3, which has been purported to directly interact with major histocompatibility complex class II (MHCII) and fibrinogen-like protein 1 (FGL1), has been the major focus for the development of therapeutic antibodies that inhibit LAG - 3 receptor- ligand interactions and restore T cell function. Here, we present a high- resolution structure of glycosylated mouse LAG - 3 ectodomain, identifying that cis- homodimerization, mediated through a network of hydrophobic residues within domain 2 (D2), is critically required for LAG - 3 function. Additionally, we found a previously unidentified key protein-glycan interaction in the dimer interface that affects the spatial orientation of the neighboring D1 domain. Mutation of LAG - 3 D2 residues reduced dimer formation, dramatically abolished LAG - 3 binding to both MHCII and FGL1 ligands, and consequentially inhibited the role of LAG - 3 in suppressing T cell responses. Intriguingly, we showed that antibodies directed against D1, D2, and D3 domains are all capable of blocking LAG - 3 dimer formation and MHCII and FGL-1 ligand binding, suggesting a potential allosteric model of LAG - 3 function tightly regulated by dimerization. Furthermore, our work reveals unique epitopes, in addition to D1, that can be targeted for immunotherapy of cancer and other human diseases.