Reactome: A Curated Pathway Database

LGI1 binds ADAM22 and ADAM23

Stable Identifier
Homo sapiens
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Leucine-rich glioma inactivated 1 (LGI1) is a secreted protein that interacts with ADAM (A Disintegrin And Metalloprotease) transmembrane proteins, and its mutations are linked to human epilepsy. Although LGI1 mutations can cause epilepsy, its precise functions in the CNS are still poorly understood. It has been suggested to be involved in controlling synaptic transmission at excitatory synapses and cerebellar development (Xie et al. 2015, Fukata et al. 2006). LGI1 binds simulatneously to the extracellular disintegrin domain of ADAM22 and ADAM23 with its EPTP (Epitempin) domain (Fukata et al. 2010) strengthening and stabilizing excitatory synapses. LGI1 interaction with ADAM23 modulates dendritic pruning and synapse elimination during development (Owuor et al. 2009, Zhou et al. 2009). LGI1 and ADAM22 are found to be part of a tripartite complex containing PSD95. PSD95 is expressed on the inner surface of postsynaptic neurons and with its third PDZ domain binds to ADAM22 cytoplasmic C-terminal ETSI-motif and with the first two PDZ domain in turn bind to stargazin. Stargazin is a transmembrane regulatory subunit of AMPA (alpha-amino-3- hydroxy-5-methylisoxazole-4-propionic acid)-receptors that is critical for AMPA-receptor trafficking and gating (Fukata et al. 2006). It has been suggested that LGI1 binds simultaneously ADAM23 and ADAM22, pulling pre and post-synaptic membranes together, physically stabilizing synapses containing these two proteins and strengthening neurotransmission in these synapses (Fukata et al. 2010). As mentioned earlier, LGI1 mutations result in ADPEAF (autosomal dominant partial epilepsy with auditory features) (OMIM 600512) (Kalachikov et al. 2002).

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