LAG3 Protein (CD223)

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LAG3 Protein (CD223)

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LAG3 Protein (CD223)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">LAG3 Protein (CD223)</th>
</tr>
<tr>
<td class="label">Approach</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Blocking antibodies</td>
<td>Prevent fibril binding/uptake</td>
</tr>
<tr>
<td class="label">Soluble LAG3</td>
<td>Decoy receptor for fibrils</td>
</tr>
<tr>
<td class="label">Small molecule inhibitors</td>
<td>Block LAG3-fibril interaction</td>
</tr>
<tr>
<td class="label">Interacting Partner</td>
<td>Type</td>
</tr>
<tr>
<td class="label">MHC Class II</td>
<td>Physiological</td>
</tr>
<tr>
<td class="label">Alpha-synuclein fibrils</td>
<td>Pathological</td>
</tr>
<tr>
<td class="label">Tau fibrils</td>
<td>Pathological</td>
</tr>
<tr>
<td class="label">Fibrinogen-like protein 1</td>
<td>Physiological</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">6 edges</a></td>
</tr>
</table>

...

LAG3 Protein (CD223)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">LAG3 Protein (CD223)</th>
</tr>
<tr>
<td class="label">Approach</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Blocking antibodies</td>
<td>Prevent fibril binding/uptake</td>
</tr>
<tr>
<td class="label">Soluble LAG3</td>
<td>Decoy receptor for fibrils</td>
</tr>
<tr>
<td class="label">Small molecule inhibitors</td>
<td>Block LAG3-fibril interaction</td>
</tr>
<tr>
<td class="label">Interacting Partner</td>
<td>Type</td>
</tr>
<tr>
<td class="label">MHC Class II</td>
<td>Physiological</td>
</tr>
<tr>
<td class="label">Alpha-synuclein fibrils</td>
<td>Pathological</td>
</tr>
<tr>
<td class="label">Tau fibrils</td>
<td>Pathological</td>
</tr>
<tr>
<td class="label">Fibrinogen-like protein 1</td>
<td>Physiological</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">6 edges</a></td>
</tr>
</table>

<div style="float: right; width: 280px; background: #f8f9fa; border: 1px solid #ddd; padding: 12px; margin: 0 0 1em 1em; font-size: 0.9em;">
<h4 style="margin-top: 0; color: #3366cc;">LAG3 (CD223)</h4>
<table style="width: 100%; border-collapse: collapse;">
<tr><td style="padding: 4px; border-bottom: 1px solid #eee;"><strong>UniProt ID</strong></td><td style="padding: 4px; border-bottom: 1px solid #eee;">[P18627](https://www.uniprot.org/uniprotkb/P18627)</td></tr>
<tr><td style="padding: 4px; border-bottom: 1px solid #eee;"><strong>Gene</strong></td><td style="padding: 4px; border-bottom: 1px solid #eee;">[LAG3](/genes/lag3)</td></tr>
<tr><td style="padding: 4px; border-bottom: 1px solid #eee;"><strong>MW</strong></td><td style="padding: 4px; border-bottom: 1px solid #eee;">~57 kDa</td></tr>
<tr><td style="padding: 4px; border-bottom: 1px solid #eee;"><strong>Location</strong></td><td style="padding: 4px; border-bottom: 1px solid #eee;">Cell membrane, immune cells</td></tr>
<tr><td style="padding: 4px; border-bottom: 1px solid #eee;"><strong>PDB</strong></td><td style="padding: 4px; border-bottom: 1px solid #eee;">[1Z2M](https://www.rcsb.org/structure/1Z2M)</td></tr>
</table>
</div>

Overview

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:[@woo2012]. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.

LAG3 Protein (CD223)

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](/diseases/parkinsons-disease).[@mao2016]

Structure and Domain Architecture

LAG3 is a type I transmembrane glycoprotein composed of:

Extracellular domain: Contains four immunoglobulin-like (Ig-like) domains (D1-D4) with structural homology to [CD4](/proteins/cd4)
Transmembrane domain: Anchors the protein to the plasma membrane
Cytoplasmic tail: Contains a unique "KIEELE" motif essential for inhibitory signaling[@workman2014]

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.

Normal 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:[@woo2012]

Immune checkpoint regulation: LAG3 negatively regulates T cell proliferation, activation, and cytokine production, acting as an immune checkpoint similar to [PD-1](/proteins/pd1)

MHC class II binding: LAG3 binds to MHC class II molecules with higher affinity than CD4

Treg function: Enhances suppressive activity of regulatory T cells

Immune tolerance: Maintains peripheral tolerance and prevents autoimmunity

Role in Neurodegeneration

Alpha-Synuclein Spreading in Parkinson's Disease

The discovery that LAG3 serves as a receptor for pathological [alpha-synuclein](/proteins/alpha-synuclein) fibrils represents a major breakthrough in understanding disease propagation in [Parkinson's disease](/diseases/parkinsons-disease):[@mao2016]

Fibril binding: LAG3 specifically binds to pathological alpha-synuclein fibrils but not monomeric alpha-synuclein

Cellular uptake: LAG3 mediates endocytosis of alpha-synuclein fibrils into [neurons](/entities/neurons) and [microglia](/cell-types/microglia-neuroinflammation)

Seeding propagation: Internalized fibrils seed the aggregation of endogenous alpha-synuclein, propagating pathology

Cell-to-cell transmission: LAG3-dependent uptake enables cell-to-cell spread of pathology

The interaction occurs primarily through the D1 domain of LAG3. Antibodies blocking this interaction prevent fibril uptake and seeding in experimental models.

Tau Pathology

LAG3 has also been implicated in [tau](/proteins/tau) spreading:[@holmes2013]

LAG3 binds to [tau](/proteins/tau) fibrils with lower affinity than alpha-synuclein
May contribute to tau propagation in certain contexts
Interaction less well-characterized than alpha-synuclein binding

Neuroinflammation

Beyond protein spreading, LAG3 contributes to neurodegeneration through immune modulation:[@mckinney2021]

Microglial activation: LAG3 expression on microglia influences inflammatory responses
T cell infiltration: LAG3 regulates T cell entry into the CNS during neuroinflammation
Immune checkpoint: Altered LAG3 signaling in neurodegenerative conditions

Therapeutic Targeting

LAG3 represents a promising therapeutic target for neurodegenerative diseases:

Anti-LAG3 Strategies for Neurodegeneration

Cancer Immunotherapy Context

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.[@tawbi2022]

Protein Interactions

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/)
[KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References

[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)](https://doi.org/10.1126/science.aah3374)

[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)](https://doi.org/10.1007/978-1-4939-1167-6_6)

[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)](https://doi.org/10.1158/0008-5472.CAN-11-1620)

[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)](https://doi.org/10.1073/pnas.1301440110)

[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)](https://doi.org/10.1038/s41582-021-00465-7)

[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)](https://doi.org/10.1056/NEJMoa2109970)

Pathway Diagram

The following diagram shows the key molecular relationships involving LAG3 Protein (CD223) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

LAG3

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kg_node_id	LAG3
entity_type	protein
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source_table	wiki_pages
wiki_page_id	wp-735d89f4d211
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-lag3'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

85%

Debates

0

Incoming

17

Outgoing

23

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

LAG3 Protein (CD223)

LAG3 Protein (CD223)

LAG3 Protein (CD223)

Overview

LAG3 Protein (CD223)

Structure and Domain Architecture

Normal Function

Role in Neurodegeneration

Alpha-Synuclein Spreading in Parkinson's Disease

Tau Pathology

Neuroinflammation

Therapeutic Targeting

Anti-LAG3 Strategies for Neurodegeneration

Cancer Immunotherapy Context

Protein Interactions

External Links

See Also

References

Pathway Diagram

💬 Discussion