| UniProt ID | [P18627](https://www.uniprot.org/uniprotkb/P18627) |
| Gene | [LAG3](/genes/lag3) |
| MW | ~57 kDa |
| Location | Cell membrane, immune cells |
| PDB | [1Z2M](https://www.rcsb.org/structure/1Z2M) |
LAG3 Protein is a protein that lag3 is primarily expressed on activated t cells, regulatory t cells (tregs), natural killer cells, and to a lesser extent on b cells and dendritic cells. its canonical functions include:[1]. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
LAG3 (Lymphocyte Activation Gene 3, also known as CD223) is a cell surface receptor protein belonging to the immunoglobulin superfamily that has emerged as a critical mediator of pathological protein spreading in neurodegenerative diseases, particularly Parkinson's disease.[2]
LAG3 is a type I transmembrane glycoprotein composed of:
The D1 domain contains a "loop" structure formed by an extra disulfide bond that is not present in CD4, giving LAG3 its distinctive binding properties. The protein forms homodimers on the cell surface, which is important for its signaling function.
LAG3 is primarily expressed on activated T cells, regulatory T cells (Tregs), natural killer cells, and to a lesser extent on B cells and dendritic cells. Its canonical functions include:[1:1]
The discovery that LAG3 serves as a receptor for pathological alpha-synuclein fibrils represents a major breakthrough in understanding disease propagation in Parkinson's disease:[2:1]
The interaction occurs primarily through the D1 domain of LAG3. Antibodies blocking this interaction prevent fibril uptake and seeding in experimental models.
LAG3 has also been implicated in tau spreading:[4]
Beyond protein spreading, LAG3 contributes to neurodegeneration through immune modulation:[5]
LAG3 represents a promising therapeutic target for neurodegenerative diseases:
| Approach | Mechanism | Development Status |
|---|---|---|
| Blocking antibodies | Prevent fibril binding/uptake | Preclinical |
| Soluble LAG3 | Decoy receptor for fibrils | Conceptual |
| Small molecule inhibitors | Block LAG3-fibril interaction | Early research |
LAG3-targeting antibodies (relatlimab) are FDA-approved for cancer immunotherapy, providing clinical validation of the target. However, these agents are designed to activate LAG3's immune checkpoint function, whereas neurodegeneration therapy would require blocking the receptor's binding to pathological proteins.[6]
| Interacting Partner | Type | Function |
|---|---|---|
| MHC Class II | Physiological | Immune regulation |
| Alpha-synuclein fibrils | Pathological | Disease spreading |
| Tau fibrils | Pathological | Potential spreading mechanism |
| Fibrinogen-like protein 1 | Physiological | Alternative ligand |
Woo SR, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72(4):917-927. doi:. 10.1158/0008-5472.CAN-11-1620. 2012. ↩︎ ↩︎
Mao X, et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. 2016;353(6307):aah3374. doi:. 10.1126/science.aah3374. 2016. ↩︎ ↩︎
Workman CJ, et al. Molecular and biochemical analysis of LAG-3. Methods Mol Biol. 2014;1192:79-91. doi:. 10.1007/978-1-4939-1167-6_6. 2014. ↩︎
Holmes BB, et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci USA. 2013;110(33):E3138-3147. doi:. 10.1073/pnas.1301440110. 2013. ↩︎
McKinney EF, et al. The immunological architecture of neurodegeneration. Nat Rev Neurol. 2021;17(5):299-312. doi:. 10.1038/s41582-021-00465-7. 2021. ↩︎
Tawbi HA, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34. doi:. 10.1056/NEJMoa2109970. 2022. ↩︎