8dgg

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Structure of glycosylated LAG-3 homodimerStructure of glycosylated LAG-3 homodimer

Structural highlights

8dgg is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.78Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LAG3_MOUSE Lymphocyte activation gene 3 protein: Inhibitory receptor on antigen activated T-cells (PubMed:12209638, PubMed:12421911, PubMed:12672063, PubMed:15100286, PubMed:15634887, PubMed:30580966). Delivers inhibitory signals upon binding to ligands, such as FGL1 (PubMed:30580966). FGL1 constitutes a major ligand of LAG3 and is responsible for LAG3 T-cell inhibitory function (PubMed:30580966). Following TCR engagement, LAG3 associates with CD3-TCR in the immunological synapse and directly inhibits T-cell activation (PubMed:12209638, PubMed:12421911, PubMed:12672063, PubMed:15100286, PubMed:15634887). May inhibit antigen-specific T-cell activation in synergy with PDCD1/PD-1, possibly by acting as a coreceptor for PDCD1/PD-1 (PubMed:21300912). Negatively regulates the proliferation, activation, effector function and homeostasis of both CD8(+) and CD4(+) T-cells (PubMed:12209638, PubMed:12421911, PubMed:12672063, PubMed:15100286, PubMed:15634887). Also mediates immune tolerance: constitutively expressed on a subset of regulatory T-cells (Tregs) and contributes to their suppressive function (PubMed:15485628). Also acts as a negative regulator of plasmacytoid dendritic cell (pDCs) activation (PubMed:19201841). Binds MHC class II (MHC-II); the precise role of MHC-II-binding is however unclear (PubMed:12209638, PubMed:12421911, PubMed:15634887).[1] [2] [3] [4] [5] [6] [7] [8] [9] 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.[10]

Publication Abstract from PubMed

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.

Structural insights reveal interplay between LAG-3 homodimerization, ligand binding, and function.,Silberstein JL, Du J, Chan KW, Frank JA, Mathews II, Kim YB, You J, Lu Q, Liu J, Philips EA, Liu P, Rao E, Fernandez D, Rodriguez GE, Kong XP, Wang J, Cochran JR Proc Natl Acad Sci U S A. 2024 Mar 19;121(12):e2310866121. doi: , 10.1073/pnas.2310866121. Epub 2024 Mar 14. PMID:38483996[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Workman CJ, Rice DS, Dugger KJ, Kurschner C, Vignali DA. Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3). Eur J Immunol. 2002 Aug;32(8):2255-63. doi:, 10.1002/1521-4141(200208)32:8<2255::AID-IMMU2255>3.0.CO;2-A. PMID:12209638 doi:<2255::AID-IMMU2255>3.0.CO;2-A http://dx.doi.org/10.1002/1521-4141(200208)32:8<2255::AID-IMMU2255>3.0.CO;2-A
  2. ↑ Workman CJ, Dugger KJ, Vignali DA. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J Immunol. 2002 Nov 15;169(10):5392-5. doi: 10.4049/jimmunol.169.10.5392. PMID:12421911 doi:http://dx.doi.org/10.4049/jimmunol.169.10.5392
  3. ↑ Workman CJ, Vignali DA. The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells. Eur J Immunol. 2003 Apr;33(4):970-9. doi: 10.1002/eji.200323382. PMID:12672063 doi:http://dx.doi.org/10.1002/eji.200323382
  4. ↑ Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali DA. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J Immunol. 2004 May 1;172(9):5450-5. doi: 10.4049/jimmunol.172.9.5450. PMID:15100286 doi:http://dx.doi.org/10.4049/jimmunol.172.9.5450
  5. ↑ Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI, Powell JD, Pardoll DM, Drake CG, Vignali DA. Role of LAG-3 in regulatory T cells. Immunity. 2004 Oct;21(4):503-13. doi: 10.1016/j.immuni.2004.08.010. PMID:15485628 doi:http://dx.doi.org/10.1016/j.immuni.2004.08.010
  6. ↑ Workman CJ, Vignali DA. Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). J Immunol. 2005 Jan 15;174(2):688-95. doi: 10.4049/jimmunol.174.2.688. PMID:15634887 doi:http://dx.doi.org/10.4049/jimmunol.174.2.688
  7. ↑ Workman CJ, Wang Y, El Kasmi KC, Pardoll DM, Murray PJ, Drake CG, Vignali DA. LAG-3 regulates plasmacytoid dendritic cell homeostasis. J Immunol. 2009 Feb 15;182(4):1885-91. doi: 10.4049/jimmunol.0800185. PMID:19201841 doi:http://dx.doi.org/10.4049/jimmunol.0800185
  8. ↑ Okazaki T, Okazaki IM, Wang J, Sugiura D, Nakaki F, Yoshida T, Kato Y, Fagarasan S, Muramatsu M, Eto T, Hioki K, Honjo T. PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice. J Exp Med. 2011 Feb 14;208(2):395-407. doi: 10.1084/jem.20100466. Epub 2011 Feb, 7. PMID:21300912 doi:http://dx.doi.org/10.1084/jem.20100466
  9. ↑ Wang J, Sanmamed MF, Datar I, Su TT, Ji L, Sun J, Chen L, Chen Y, Zhu G, Yin W, Zheng L, Zhou T, Badri T, Yao S, Zhu S, Boto A, Sznol M, Melero I, Vignali DAA, Schalper K, Chen L. Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3. Cell. 2019 Jan 10;176(1-2):334-347.e12. doi: 10.1016/j.cell.2018.11.010. Epub, 2018 Dec 20. PMID:30580966 doi:http://dx.doi.org/10.1016/j.cell.2018.11.010
  10. ↑ Andreae S, Piras F, Burdin N, Triebel F. Maturation and activation of dendritic cells induced by lymphocyte activation gene-3 (CD223). J Immunol. 2002 Apr 15;168(8):3874-80. doi: 10.4049/jimmunol.168.8.3874. PMID:11937541 doi:http://dx.doi.org/10.4049/jimmunol.168.8.3874
  11. ↑ Silberstein JL, Du J, Chan KW, Frank JA, Mathews II, Kim YB, You J, Lu Q, Liu J, Philips EA, Liu P, Rao E, Fernandez D, Rodriguez GE, Kong XP, Wang J, Cochran JR. Structural insights reveal interplay between LAG-3 homodimerization, ligand binding, and function. Proc Natl Acad Sci U S A. 2024 Mar 19;121(12):e2310866121. PMID:38483996 doi:10.1073/pnas.2310866121

8dgg, resolution 3.78Å

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