ADAM22 Protein
Overview
<table class="infobox infobox-protein">
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<th class="infobox-header" colspan="2">ADAM22 Protein</th>
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<td class="label">Symbol</td>
<td><strong>ADAM22</strong></td>
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<td class="label">Full Name</td>
<td>ADAM22</td>
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<td class="label">Type</td>
<td>Protein</td>
</tr>
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<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=ADAM22" target="_blank">Search UniProt</a></td>
</tr>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
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</table>
[ADAM22](/genes/adam22) is a catalytically inactive member of the ADAM (a disintegrin and metalloproteinase) family that functions primarily as a neuronal synaptic receptor and scaffold organizer rather than a protease. Its best-characterized role is as a postsynaptic binding partner for LGI1 within the LGI1-ADAM22-ADAM23 trans-synaptic complex.[@yamagata2019][@fukata2021]
Although ADAM22 biology is classically studied in epilepsy, it is highly relevant to NeuroWiki’s mechanistic framework because it governs excitatory synaptic alignment, AMPA receptor organization, and circuit stability, all of which are frequently disrupted in neurodegenerative syndromes.[@yamagata2019][@guella2022]
Structural and Molecular Function
...ADAM22 Protein
Overview
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">ADAM22 Protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>ADAM22</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>ADAM22</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=ADAM22" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
[ADAM22](/genes/adam22) is a catalytically inactive member of the ADAM (a disintegrin and metalloproteinase) family that functions primarily as a neuronal synaptic receptor and scaffold organizer rather than a protease. Its best-characterized role is as a postsynaptic binding partner for LGI1 within the LGI1-ADAM22-ADAM23 trans-synaptic complex.[@yamagata2019][@fukata2021]
Although ADAM22 biology is classically studied in epilepsy, it is highly relevant to NeuroWiki’s mechanistic framework because it governs excitatory synaptic alignment, AMPA receptor organization, and circuit stability, all of which are frequently disrupted in neurodegenerative syndromes.[@yamagata2019][@guella2022]
Structural and Molecular Function
Structural studies show that LGI1 and ADAM22 assemble into higher-order complexes that bridge pre- and postsynaptic compartments. This architecture supports nanoscale alignment between transmitter release machinery and glutamate receptor nanodomains, improving transmission precision and reliability.[@yamagata2019][@fukata2021]
ADAM22 also couples to intracellular MAGUK scaffold proteins (for example PSD-95 family members), enabling assembly of receptor-rich postsynaptic complexes. Disrupting ADAM22-MAGUK interaction destabilizes synaptic nano-organization and impairs excitatory signaling fidelity.[@fukata2021]
Key mechanistic outputs of intact ADAM22 signaling include:
- stabilization of glutamatergic postsynaptic architecture,
- support of AMPA receptor cluster organization,
- reduction of pathological hyperexcitability risk.[@fukata2021][@ohkawa2013]
Human Disease Genetics and Autoimmune Evidence
Biallelic ADAM22 pathogenic variants are associated with developmental and epileptic encephalopathy, including refractory seizures and progressive neurodevelopmental impairment, indicating that ADAM22 is a core neuronal resilience factor in humans.[@guella2022]
A complementary disease model comes from anti-LGI1 autoimmune encephalitis. In this condition, patient antibodies disrupt LGI1-ADAM22/23 interactions, with downstream effects on AMPA receptor organization and hippocampal excitability.[@ohkawa2013][@irani2010] This convergence between monogenic and autoimmune mechanisms strongly supports ADAM22 as a central excitability-control hub.
Relevance to Neurodegeneration
ADAM22 is not currently a canonical monogenic cause of major adult neurodegenerative dementias, but several aspects of its biology intersect directly with neurodegenerative mechanisms:
Synaptic vulnerability: ADAM22-dependent nanoalignment supports excitatory synapse integrity, a process impaired early in cognitive decline disorders.[@fukata2021]
Network instability: Hyperexcitability and epileptiform activity are recognized in subsets of neurodegenerative patients; ADAM22 pathway dysfunction offers a mechanistic framework for this phenotype.[@yamagata2019][@ohkawa2013]
Protein-complex fragility: Disease states that alter scaffold proteins or membrane trafficking may secondarily destabilize LGI1-ADAM22 signaling, amplifying excitotoxic stress.[@fukata2021][@guella2022]For these reasons, ADAM22 should be tracked as a mechanistic node linking synapse architecture, excitability, and disease progression dynamics.
Translational Considerations
Potential translational directions include:
- biomarker programs measuring LGI1-ADAM22 pathway integrity in patient-derived neuronal systems,
- interventions that stabilize postsynaptic scaffold coupling in high-hyperexcitability phenotypes,
- precision stratification of neurodegenerative cohorts with comorbid seizure or network-instability signatures for ADAM22-axis studies.[@fukata2021][@guella2022]
Any therapeutic strategy targeting this axis should preserve physiological synaptic alignment while avoiding excessive suppression of adaptive plasticity.
See Also
- [LGI1 Protein](/proteins/lgi1-protein)
- [AMPA Receptors](/proteins/ampa-receptor)
- [Synaptic Dysfunction](/mechanisms/synaptic-dysfunction)
- [Neuroinflammation](/mechanisms/neuroinflammation)
External Links
- [UniProt: ADAM22 (Q9P0K1)](https://www.uniprot.org/uniprotkb/Q9P0K1/entry)
- [NCBI Gene: ADAM22](https://www.ncbi.nlm.nih.gov/gene/53616)
References
[Yamagata A, Fukai S, Insights into the mechanisms of epilepsy from structural biology of LGI1-ADAM22 (2019)](https://pubmed.ncbi.nlm.nih.gov/31432233/)
Fukata Y, Lovero KL, Iwanaga T, et al, LGI1-ADAM22-MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention (2021)
[Guella I, McKenzie MB, Evans DM, et al, Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy (2022)](https://pubmed.ncbi.nlm.nih.gov/35373813/)
[Ohkawa T, Fukata Y, Yamasaki M, et al, Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors (2013)](https://pubmed.ncbi.nlm.nih.gov/24227725/)
[Irani SR, Alexander S, Waters P, et al, Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels (2010)](https://pubmed.ncbi.nlm.nih.gov/20580615/)AlphaFold Structure
AlphaFold DB provides a predicted structure for ADAM22 / UniProt Q9P0K1 (model version 6): https://alphafold.ebi.ac.uk/entry/Q9P0K1.
AlphaFold reports a mean pLDDT confidence score of 73.19, indicating confident backbone placement for much of the model, with lower-confidence regions possible.
InterPro annotations highlight EGF-like domain domain (700-711); Peptidase M12B, ADAM/reprolysin domain (239-438); Disintegrin domain domain (444-531).
PDB coordinates: https://alphafold.ebi.ac.uk/files/AF-Q9P0K1-F1-model_v6.pdb mmCIF coordinates: https://alphafold.ebi.ac.uk/files/AF-Q9P0K1-F1-model_v6.cif.
Use the prediction as structural context for target assessment; local low-pLDDT segments may reflect disorder, flexible linkers, or unresolved domain orientation rather than a stable fold.