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

John L SilbersteinJasper DuKun-Wei ChanJessica A FrankIrimpan I MathewsYong Bin KimJia YouQiao LuJia LiuElliot A PhilipsPhillip LiuEric RaoDaniel FernándezGrayson E RodriguezXiang-Peng KongJun WangJennifer R Cochran
Published in: Proceedings of the National Academy of Sciences of the United States of America (2024)
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.
Keyphrases
  • high resolution
  • mass spectrometry
  • gene expression
  • endothelial cells
  • signaling pathway
  • risk assessment
  • young adults
  • drug delivery
  • cancer therapy
  • tandem mass spectrometry