ADAM22

ADAM22 is a catalytically inactive transmembrane member of the ADAM family that functions as a postsynaptic receptor for secreted LGI-family ligands, organizing synaptic nanoarchitecture and supporting myelination in the peripheral nervous system. Its metalloprotease-like ectodomain binds the EPTP domain of LGI1, forming 2:2 and 3:3 trans-synaptic assemblies that enhance AMPA receptor–mediated transmission and establish transsynaptic nanoalignment of release machinery with postsynaptic receptor clusters, while its cytoplasmic PDZ-binding motif recruits PSD-95-family MAGUKs to condense postsynaptic density nanodomains (PMID:16990550, PMID:33397806, PMID:29670100, PMID:40601686). On myelinated axons, ADAM22 serves as the neuronal receptor for Schwann cell–secreted LGI4, driving peripheral nerve myelination, and localizes to juxtaparanodes and axon initial segments where it recruits MAGUKs to Kv1 channel complexes (PMID:20220021, PMID:20089912). Surface expression is controlled by PKA-dependent phosphorylation that promotes 14-3-3 binding, masking ER retention signals and protecting ADAM22–LGI1 complexes from endocytic degradation (PMID:16868027, PMID:34910912). Biallelic loss-of-function ADAM22 variants cause developmental and epileptic encephalopathy through defective surface expression, impaired LGI1 binding, and/or loss of PSD-95 interaction (PMID:27066583, PMID:35373813).

1. 2002 Low

   Identification of 14-3-3β as a cytoplasmic binding partner of ADAM22 provided the first clue that intracellular signaling or trafficking regulation controls ADAM22 function.

   Evidence Yeast two-hybrid and co-immunoprecipitation mapping 14-3-3β binding to the last 28 residues of ADAM22's cytoplasmic tail

   PMID:18762889

   Open questions at the time

   • Binding confirmed by yeast two-hybrid and Co-IP only; no independent lab replication
   • Functional consequence of 14-3-3 binding on ADAM22 trafficking unknown at this stage
2. 2005 High

   Genetic ablation of ADAM22 in mice established that it is essential for nervous system function, causing lethal seizures, ataxia, and peripheral nerve hypomyelination — defining the physiological processes requiring ADAM22.

   Evidence ADAM22 knockout mice with histological, behavioral, and myelination analysis

   PMID:15876356

   Open questions at the time

   • Molecular mechanism by which ADAM22 prevents seizures and promotes myelination unknown
   • Whether ADAM22 acts cell-autonomously in neurons vs. glia not resolved
3. 2006 High

   Discovery that ADAM22 is the postsynaptic receptor for secreted LGI1 and that this interaction enhances AMPA receptor–mediated synaptic transmission provided the core functional paradigm for the gene.

   Evidence Co-immunoprecipitation, cell-surface binding, and hippocampal slice electrophysiology

   PMID:16990550

   Open questions at the time

   • Structural basis of LGI1–ADAM22 binding not yet known
   • Whether LGI1 is the only relevant ligand at synapses unresolved
4. 2006 High

   Phosphorylation-dependent 14-3-3 binding was shown to mask ER retention signals, explaining how ADAM22 surface expression is regulated — answering the trafficking mechanism question.

   Evidence Yeast two-hybrid, Co-IP, mutagenesis, and cell-surface localization assays showing 14-3-3 binding site mutants fail to reach the surface unless ER retention motifs are simultaneously deleted

   PMID:16868027

   Open questions at the time

   • Kinase identity responsible for phosphorylation not yet identified
   • In vivo relevance of the trafficking mechanism not tested
5. 2008 Medium

   Demonstration that both LGI1 and LGI4 bind ADAM22 expanded the receptor's ligand repertoire beyond a single LGI family member, suggesting a broader role for ADAM22 in LGI-mediated signaling.

   Evidence Immunoprecipitation from mouse brain and quantitative cell-ELISA

   PMID:18974846

   Open questions at the time

   • Physiological contexts in which LGI4–ADAM22 interaction matters not yet defined
6. 2009 High

   The crystal structure of the ADAM22 ectodomain revealed a compact four-domain arrangement and explained why the metalloprotease domain is catalytically inactive — the active site is occluded and lacks catalytic residues.

   Evidence X-ray crystallography and isothermal titration calorimetry

   PMID:19692335

   Open questions at the time

   • Structure of the ADAM22–LGI1 complex not yet resolved
   • Roles of bound calcium ions in vivo unknown
7. 2010 High

   Two studies resolved ADAM22's roles outside the synapse: at juxtaparanodes it recruits MAGUKs to Kv1 channel complexes, and on axons it serves as the receptor for Schwann cell–secreted LGI4 to drive peripheral myelination.

   Evidence IP-MS of Kv1.2 complexes plus multiple null mouse lines (juxtaparanode study); direct binding assays plus conditional knockout mice and neuron–Schwann cell co-cultures (myelination study)

   PMID:20089912 PMID:20220021

   Open questions at the time

   • Whether ADAM22 acts differently at juxtaparanodes vs. AIS vs. synapses mechanistically
   • How ADAM22 cooperates with Caspr2 at juxtaparanodes unclear
8. 2013 High

   LGI1 autoantibodies in limbic encephalitis were shown to disrupt LGI1–ADAM22 interaction specifically, and a soluble ADAM22 ectodomain acting as a dominant negative reduced synaptic AMPA receptor clusters — linking autoimmune disruption of the ADAM22 pathway to disease.

   Evidence ELISA, cell-surface binding, dominant-negative ectodomain experiments in hippocampal neurons, LGI1 KO mouse analysis

   PMID:24227725

   Open questions at the time

   • Whether ADAM22 is itself a direct autoantibody target not fully resolved
   • Downstream signaling events after LGI1–ADAM22 disruption not characterized
9. 2015 High

   Genetic epistasis experiments established that LGI1 signals exclusively through ADAM22 to set postsynaptic strength and that the ADAM22-PDZ interaction is required for PSD-95 to potentiate synaptic transmission, clarifying the receptor–scaffold signaling hierarchy.

   Evidence Single-cell electroporation, hippocampal slice electrophysiology, and KO/rescue experiments

   PMID:26178195

   Open questions at the time

   • How LGI1 binding to ADAM22 transduces a signal intracellularly remains uncharacterized
   • Whether ADAM22 signals through any pathway independent of MAGUKs unknown
10. 2016 Medium

    Patient mutations and ADLTE-causing LGI1 variants converged to show that disruption of the LGI1–ADAM22 binding interface or the ADAM22–PSD-95 interface individually suffice to cause epilepsy, genetically dissecting the two functional arms of ADAM22.

    Evidence Exome sequencing with functional binding assays for ADAM22 patient variants; immunofluorescence and Co-IP for LGI1 ADLTE missense mutations; live-cell imaging of LGI1–ADAM22 co-transport to the AIS

    PMID:27066583 PMID:27760137 PMID:30598502

    Open questions at the time

    • Genotype-phenotype correlation across the full mutation spectrum incomplete
    • Whether partial loss of one interaction arm has a milder phenotype than loss of both not systematically tested in vivo
11. 2018 High

    The crystal structure of the LGI1–ADAM22 complex revealed a 2:2 heterotetrameric assembly mediated by the LGI1-EPTP domain contacting the ADAM22 metalloprotease domain, and showed that the pathogenic R474Q mutation disrupts the LGI1–LGI1 interface needed for higher-order assembly.

    Evidence X-ray crystallography, mutagenesis, and a mouse model of familial epilepsy

    PMID:29670100

    Open questions at the time

    • Whether trans-synaptic bridging involves higher-order assemblies beyond 2:2 unknown
    • Structural basis of ADAM22 interaction with other LGI family members not determined
12. 2021 High

    Two discoveries resolved the downstream consequence and upstream regulation of ADAM22: knock-in mice lacking the ADAM22–MAGUK interaction showed that ADAM22 governs transsynaptic nanoalignment of PSD-95 condensates with release sites, and PKA-dependent dual phosphorylation was identified as the signal promoting 14-3-3 binding that protects ADAM22–LGI1 complexes from endocytic degradation.

    Evidence ADAM22 PDZ-binding motif knock-in mice with super-resolution imaging and electrophysiology; PKA pharmacology and ADAM22/LGI1 hypomorphic mouse series with endocytosis assays

    PMID:33397806 PMID:34910912

    Open questions at the time

    • Whether PKA regulation of ADAM22 is activity-dependent at synapses not shown
    • How approximately 10% of ADAM22 suffices to prevent seizures mechanistically unexplained
13. 2022 Medium

    Systematic functional analysis of 19 patient ADAM22 variants confirmed biallelic loss-of-function causes developmental and epileptic encephalopathy through three distinct molecular mechanisms: defective surface expression, impaired LGI1 binding, and/or impaired PSD-95 interaction.

    Evidence Cell-surface expression and Co-IP assays across 19 transfected patient variants

    PMID:35373813

    Open questions at the time

    • Patient variants tested only in heterologous cells, not in neuronal systems
    • Quantitative thresholds of each interaction arm needed to prevent seizures not defined
14. 2025 High

    Cryo-EM structures revealed a 3:3 heterohexameric LGI1–ADAM22 assembly at near-atomic resolution, extending the 2:2 model and demonstrating structural flexibility of the complex in solution.

    Evidence Cryo-EM at 2.78 Å and 3.79 Å resolution with high-speed atomic force microscopy validation

    PMID:40601686

    Open questions at the time

    • Whether the 3:3 complex forms in vivo at synapses not demonstrated
    • How the flexible 3:3 assembly bridges pre- and postsynaptic membranes structurally unresolved

• Key unresolved questions include how LGI1 binding to the ADAM22 ectodomain transduces an intracellular signal beyond scaffold recruitment, whether the 3:3 complex operates as the physiological trans-synaptic bridge, and whether activity-dependent regulation of ADAM22 phosphorylation tunes synaptic strength.
• No intracellular signaling cascade downstream of LGI1–ADAM22 binding identified
• In vivo stoichiometry and architecture of the trans-synaptic complex unknown
• Whether ADAM22 has synaptic functions independent of LGI ligands not tested