LAG3
entrez
3902
canonical
uniprot
P18627
canonical
ensembl
ENSG00000089692
resolver
ensp
ENSP00000203629
resolver
ensp
ENSP00000557856
resolver
ensp
ENSP00000790183
resolver
genesymbol
LAG3
resolver
genesymbol_syn
FDC
resolver
hgnc
HGNC:6476
resolver
uniprot
A8K7T9
resolver
uniprot
Q7Z643
resolver
uniprot_entry
LAG3_HUMAN
resolver
uniprot_sec
A8K7T9
resolver
uniprot_sec
Q7Z643
resolver
activity_regulation
ACTIVITY REGULATION: Inhibited by relatlimab, a monoclonal antibody, which shows clinical efficacy in the treatment of cancers (PubMed:35981087, PubMed:40101708). Relatlimab prevents ubiquitination by CBL or CBLB and activation (PubMed:40101708). Inhibited by favezelimab, a therapeutic antibody (PubMed:37619561). {ECO:0000269|PubMed:35981087, ECO:0000269|PubMed:37619561, ECO:0000269|PubMed:40101708}.
uniprot
proteins
amino_acid_sequence
MWEAQFLGLLFLQPLWVAPVKPLQPGAEVPVVWAQEGAPAQLPCSPTIPLQDLSLLRRAGVTWQHQPDSGPPAAAPGHPLAPGPHPAAPSSWGPRPRRYTVLSVGPGGLRSGRLPLQPRVQLDERGRQRGDFSLWLRPARRADAGEYRAAVHLRDRALSCRLRLRLGQASMTASPPGSLRASDWVILNCSFSRPDRPASVHWFRNRGQGRVPVRESPHHHLAESFLFLPQVSPMDSGPWGCILTYRDGFNVSIMYNLTVLGLEPPTPLTVYAGAGSRVGLPCRLPAGVGTRSFLTAKWTPPGGGPDLLVTGDNGDFTLRLEDVSQAQAGTYTCHIHLQEQQLNATVTLAIITVTPKSFGSPGSLGKLLCEVTPVSGQERFVWSSLDTPSQRSFSGPWLEAQEAQLLSQPWQCQLYQGERLLGAAVYFTELSSPGAQRSGRAPGALPAGHLLLFLILGVLSLLLLVTGAFGFHLWRRQWRPRRFSALEQGIHPPQAQSKIEELEQEPEPEPEPEPEPEPEPEPEQL
uniprot
proteins
function
FUNCTION: [Lymphocyte activation gene 3 protein]: Inhibitory receptor on antigen activated T-cells (PubMed:20421648, PubMed:35761082, PubMed:7805750, PubMed:8647185). Delivers inhibitory signals upon binding to ligands, such as MHC class II, its main ligand present at the surface of antigen-presenting cells (APCs), and FGL1, which is secreted by hepatocytes and certain types of tumor cells (PubMed:30580966, PubMed:32920841, PubMed:35761082, PubMed:39671469, PubMed:7589152, PubMed:8647185, PubMed:9159144). Ligand-binding initiates a signaling that inhibits the T-cell receptor (TCR) in the immunological synapse, preventing T-cell activation (PubMed:40101708). Mechanistically, ligand-binding promotes (1) ubiquitination of the KIEELE motif, unleashing the RRFSALE motif from the membrane and (2) leading to the formation of condensates with the TCR component CD3E, thereby disrupting the association between CD3E and LCK and preventing TCR activation (PubMed:40101708, PubMed:40592325). May inhibit antigen-specific T-cell activation in synergy with PDCD1/PD-1 (By similarity). Negatively regulates the proliferation, activation, effector function and homeostasis of both CD8(+) and CD4(+) T-cells (PubMed:20421648, PubMed:7805750, PubMed:8647185). 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). {ECO:0000250|UniProtKB:Q61790, ECO:0000269|PubMed:20421648, ECO:0000269|PubMed:30580966, ECO:0000269|PubMed:32920841, ECO:0000269|PubMed:35761082, ECO:0000269|PubMed:39671469, ECO:0000269|PubMed:40101708, ECO:0000269|PubMed:40592325, ECO:0000269|PubMed:7589152, ECO:0000269|PubMed:7805750, ECO:0000269|PubMed:8647185, ECO:0000269|PubMed:9159144}.; FUNCTION: The LAG3-mediated inhibitory pathway is exploited by tumors to attenuate anti-tumor immunity and escape destruction by the immune system, thereby facilitating tumor survival (PubMed:35981087, PubMed:40101708). The blockage of the LAG3- and PDCD1-mediated pathways results in the reversal of the exhausted T-cell phenotype and the normalization of the anti-tumor response, providing a rationale for cancer immunotherapy (PubMed:35981087, PubMed:40101708). {ECO:0000269|PubMed:35981087, ECO:0000269|PubMed:40101708}.; FUNCTION: [Secreted lymphocyte activation gene 3 protein]: 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. {ECO:0000250|UniProtKB:Q61790}.
uniprot
proteins
mass_dalton
57449
uniprot
proteins
mutagenesis
MUTAGEN 35; /note="Q->A: Does not affect binding to MHC class II (MHC-II)."; /evidence="ECO:0000269|PubMed:9159144"; MUTAGEN 52; /note="D->A: Reduced binding to MHC class II (MHC-II)."; /evidence="ECO:0000269|PubMed:9159144"; MUTAGEN 78; /note="H->A: Reduced binding to MHC class II (MHC-II)."; /evidence="ECO:0000269|PubMed:9159144"; MUTAGEN 78; /note="H->F: Does not significantly affect binding to MHC class II (MHC-II)."; /evidence="ECO:0000269|PubMed:9159144"; MUTAGEN 85; /note="H->A,F: Does not affect binding to MHC class II (MHC-II)."; /evidence="ECO:0000269|PubMed:9159144"; MUTAGEN 95; /note="R->E: Increased binding to MHC class II (MHC-II)."; /evidence="ECO:0000269|PubMed:9159144"; MUTAGEN 97; /note="R->A,E: Increased binding to MHC class II (MHC-II)."; /evidence="ECO:0000269|PubMed:9159144"; MUTAGEN 98; /note="R->E: Increased binding to MHC class II (MHC-II)."; /evidence="ECO:0000269|PubMed:9159144"; MUTAGEN 99; /note="Y->F: Abolishes binding to MHC class II (MHC-II) without affecting interaction with FGL1."; /evidence="ECO:0000269|PubMed:30580966, ECO:0000269|PubMed:9159144"; MUTAGEN 104; /note="V->E: Decreased binding to FGL1."; /evidence="ECO:0000269|PubMed:39671469"; MUTAGEN 110; /note="R->A: Reduced binding to MHC class II (MHC-II)."; /evidence="ECO:0000269|PubMed:9159144"; MUTAGEN 113; /note="R->E: Decreased binding to FGL1."; /evidence="ECO:0000269|PubMed:39671469"; MUTAGEN 117; /note="Q->K: Decreased binding to FGL1."; /evidence="ECO:0000269|PubMed:39671469"; MUTAGEN 120; /note="V->D: Decreased binding to FGL1."; /evidence="ECO:0000269|PubMed:39671469"; MUTAGEN 125; /note="R->A: Reduced binding to MHC class II (MHC-II)."; /evidence="ECO:0000269|PubMed:9159144"; MUTAGEN 129; /note="R->K: Does not affect binding to MHC class II (MHC-II)."; /evidence="ECO:0000269|PubMed:9159144"; MUTAGEN 131; /note="D->A: Reduced binding to MHC class II (MHC-II)."; /evidence="ECO:0000269|PubMed:9159144"; MUTAGEN 137; /note="R->A: Reduced binding to MHC class II (MHC-II)."; /evidence="ECO:0000269|PubMed:9159144"; MUTAGEN 155..156; /note="DR->AA: Slightly affects binding to MHC class II (MHC-II)."; /evidence="ECO:0000269|PubMed:9159144"; MUTAGEN 219..220; /note="HH->AA: Decreased binding to FGL1."; /evidence="ECO:0000269|PubMed:39671469"; MUTAGEN 225..226; /note="FL->AA: Decreased binding to FGL1."; /evidence="ECO:0000269|PubMed:39671469"; MUTAGEN 228..229; /note="LP->AA: Decreased binding to FGL1."; /evidence="ECO:0000269|PubMed:39671469"; MUTAGEN 244..245; /note="TY->AA: Decreased binding to FGL1."; /evidence="ECO:0000269|PubMed:39671469"; MUTAGEN 247; /note="D->L: Does not affect binding to MHC class II (MHC-II)."; /evidence="ECO:0000269|PubMed:9159144"; MUTAGEN 250..252; /note="NVS->AAA: Decreased binding to FGL1."; /evidence="ECO:0000269|PubMed:39671469"; MUTAGEN 483..486; /note="FSAL->ASAA: Abolished formation of condensates with CD3E."; /evidence="ECO:0000269|PubMed:40592325"; MUTAGEN 483; /note="F->A: Abolished ability to prevent TCR activation."; /evidence="ECO:0000269|PubMed:37788323"; MUTAGEN 486; /note="L->A: Abolished ability to prevent TCR activation."; /evidence="ECO:0000269|PubMed:37788323"; MUTAGEN 487; /note="E->A: Decreased ability to prevent TCR activation."; /evidence="ECO:0000269|PubMed:37788323"; MUTAGEN 487; /note="E->EAAAAAAAAAA: In 10AA; prevents activation of the RRFSALE motif and ability to inhibit TCR activation."; /evidence="ECO:0000269|PubMed:40101708"; MUTAGEN 498; /note="K->R: Abolished ubiquitination and ability to prevent TCR activation."; /evidence="ECO:0000269|PubMed:40101708
uniprot
proteins
post_translational_modification
PTM: [Lymphocyte activation gene 3 protein]: Ubiquitinated by CBL and CBLB in response to ligand-binding, initiating a signaling that prevents TCR activation: ubiquitination at Lys-498 via 'Lys-63'-linked ubiquitin chains unleashes the RRFSALE motif from the membrane (PubMed:40101708). MHC class II and membrane-bound FGL1 promote ubiquitination by CBL and CBLB; in contrast secreted FGL1 is not able to trigger LAG3 ubiquitination (PubMed:40101708). {ECO:0000269|PubMed:40101708}.; PTM: [Lymphocyte activation gene 3 protein]: Proteolytically cleaved by ADAM10 and ADAM17 within the connecting peptide region, leading to release of Secreted lymphocyte activation gene 3 protein (sLAG-3). ADAM10 mediates constitutive cleavage, but cleavage increases following T-cell activation, whereas shedding by ADAM17 is induced by TCR signaling in a PRKCQ-dependent manner. {ECO:0000250|UniProtKB:Q61790}.
uniprot
proteins
protein_family
LAG3 family
uniprot
proteins
pubmed
1380059
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16541075
uniprot
proteins
pubmed
1692078
uniprot
proteins
pubmed
20421648
uniprot
proteins
pubmed
30580966
uniprot
proteins
pubmed
32920841
uniprot
proteins
pubmed
35761082
uniprot
proteins
pubmed
35981087
uniprot
proteins
pubmed
37619561
uniprot
proteins
pubmed
37788323
uniprot
proteins
pubmed
39671469
uniprot
proteins
pubmed
40101708
uniprot
proteins
pubmed
40592325
uniprot
proteins
pubmed
7589152
uniprot
proteins
pubmed
7805750
uniprot
proteins
pubmed
8647185
uniprot
proteins
pubmed
9159144
uniprot
proteins
pubmed
9634475
uniprot
proteins
sequence_length
525
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: [Lymphocyte activation gene 3 protein]: Cell membrane {ECO:0000269|PubMed:1380059, ECO:0000269|PubMed:1692078, ECO:0000269|PubMed:35761082, ECO:0000269|PubMed:9634475}; Single-pass type I membrane protein {ECO:0000269|PubMed:35761082}. Note=Clusters on the T-cell surface following ligand-binding. {ECO:0000269|PubMed:35761082}.; SUBCELLULAR LOCATION: [Secreted lymphocyte activation gene 3 protein]: Secreted {ECO:0000250|UniProtKB:Q61790}. Note=Produced following cleavage of the main chain. {ECO:0000250|UniProtKB:Q61790}.
uniprot
proteins
transmembrane_region
TRANSMEM 451..471; /note="Helical"; /evidence="ECO:0000255
uniprot
proteins