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Structure of human LAG3 domains 3-4 in complex with antibody single chain-variable fragment
Structural highlights
FunctionLAG3_HUMAN Lymphocyte activation gene 3 protein: Inhibitory receptor on antigen activated T-cells (PubMed:7805750, PubMed:8647185, PubMed:20421648). Delivers inhibitory signals upon binding to ligands, such as FGL1 (By similarity). FGL1 constitutes a major ligand of LAG3 and is responsible for LAG3 T-cell inhibitory function (By similarity). Following TCR engagement, LAG3 associates with CD3-TCR in the immunological synapse and directly inhibits T-cell activation (By similarity). May inhibit antigen-specific T-cell activation in synergy with PDCD1/PD-1, possibly by acting as a coreceptor for PDCD1/PD-1 (By similarity). Negatively regulates the proliferation, activation, effector function and homeostasis of both CD8(+) and CD4(+) T-cells (PubMed:7805750, PubMed:8647185, PubMed:20421648). Also mediates immune tolerance: constitutively expressed on a subset of regulatory T-cells (Tregs) and contributes to their suppressive function (By similarity). Also acts as a negative regulator of plasmacytoid dendritic cell (pDCs) activation (By similarity). Binds MHC class II (MHC-II); the precise role of MHC-II-binding is however unclear (PubMed:8647185).[UniProtKB:Q61790][1] [2] [3] May function as a ligand for MHC class II (MHC-II) on antigen-presenting cells (APC), promoting APC activation/maturation and driving Th1 immune response.[UniProtKB:Q61790] Publication Abstract from PubMedThe immune checkpoint receptor lymphocyte activation gene 3 protein (LAG3) inhibits T cell function upon binding to major histocompatibility complex class II (MHC class II) or fibrinogen-like protein 1 (FGL1). Despite the emergence of LAG3 as a target for next-generation immunotherapies, we have little information describing the molecular structure of the LAG3 protein or how it engages cellular ligands. Here we determined the structures of human and murine LAG3 ectodomains, revealing a dimeric assembly mediated by Ig domain 2. Epitope mapping indicates that a potent LAG3 antagonist antibody blocks interactions with MHC class II and FGL1 by binding to a flexible 'loop 2' region in LAG3 domain 1. We also defined the LAG3-FGL1 interface by mapping mutations onto structures of LAG3 and FGL1 and established that FGL1 cross-linking induces the formation of higher-order LAG3 oligomers. These insights can guide LAG3-based drug development and implicate ligand-mediated LAG3 clustering as a mechanism for disrupting T cell activation. LAG3 ectodomain structure reveals functional interfaces for ligand and antibody recognition.,Ming Q, Celias DP, Wu C, Cole AR, Singh S, Mason C, Dong S, Tran TH, Amarasinghe GK, Ruffell B, Luca VC Nat Immunol. 2022 Jun 27. pii: 10.1038/s41590-022-01238-7. doi:, 10.1038/s41590-022-01238-7. PMID:35761082[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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