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 journalArticle

Abstract

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
JournalNeuron
Volume86
Issue number2
DOIs
StatePublished - Apr 22 2015

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Human Immunodeficiency Virus gag Gene Products
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Retroelements
Neuronal Plasticity
Immediate-Early Genes
Capsid
Consensus Sequence
Synapses
Vertebrates
Schizophrenia
Learning
Peptides
Genes
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Structural basis of arc binding to synaptic proteins : Implications for cognitive disease. / Zhang, Wenchi; Wu, Jing; Ward, Matthew D.; Yang, Sunggu; Chuang, Yang An; Xiao, Meifang; Li, Ruojing; Leahy, Daniel J.; Worley, Paul F.

In: Neuron, Vol. 86, No. 2, 22.04.2015, p. 490-500.

Research output: Contribution to journalArticle

Zhang, Wenchi ; Wu, Jing ; Ward, Matthew D. ; Yang, Sunggu ; Chuang, Yang An ; Xiao, Meifang ; Li, Ruojing ; Leahy, Daniel J. ; Worley, Paul F. / Structural basis of arc binding to synaptic proteins : Implications for cognitive disease. In: Neuron. 2015 ; Vol. 86, No. 2. pp. 490-500.
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