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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