Neuron
Volume 86, Issue 2, 22 April 2015, Pages 490-500
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Article
Structural Basis of Arc Binding to Synaptic Proteins: Implications for Cognitive Disease

https://doi.org/10.1016/j.neuron.2015.03.030Get rights and content
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Highlights

  • Arc arises by domestication of a Ty3/Gypsy retrotransposon

  • Arc N-lobe binds TARPγ2 and is required for Arc-dependent scaling of AMPA receptors

  • Arc binding consensus motif is present in synaptic genes implicated in schizophrenia

  • Arc N-lobe binding can be inhibited by small chemical molecules

Summary

Arc is a cellular immediate-early gene (IEG) that functions at excitatory synapses and is required for learning and memory. We report crystal structures of Arc subdomains that form a bi-lobar architecture remarkably similar to the capsid domain of human immunodeficiency virus (HIV) gag protein. Analysis indicates Arc originated from the Ty3/Gypsy retrotransposon family and was “domesticated” in higher vertebrates for synaptic functions. The Arc N-terminal lobe evolved a unique hydrophobic pocket that mediates intermolecular binding with synaptic proteins as resolved in complexes with TARPγ2 (Stargazin) and CaMKII peptides and is essential for Arc’s synaptic function. A consensus sequence for Arc binding identifies several additional partners that include genes implicated in schizophrenia. Arc N-lobe binding is inhibited by small chemicals suggesting Arc’s synaptic action may be druggable. These studies reveal the remarkable evolutionary origin of Arc and provide a structural basis for understanding Arc’s contribution to neural plasticity and disease.

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