Structural basis of arc binding to synaptic proteins: Implications for cognitive disease

Wenchi Zhang, Jing Wu, Matthew D. Ward, Sunggu Yang, Yang An Chuang, Meifang Xiao, Ruojing Li, Daniel J Leahy, Paul F. Worley

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)490-500
Number of pages11
Issue number2
StatePublished - Apr 22 2015

ASJC Scopus subject areas

  • Neuroscience(all)


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