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

Neuron. 2015 Apr 22;86(2):490-500. doi: 10.1016/j.neuron.2015.03.030. Epub 2015 Apr 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Calcium Channels / chemistry
  • Calcium Channels / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cognition / physiology
  • Cognition Disorders / metabolism*
  • Genes, Immediate-Early / physiology*
  • Homeostasis / physiology
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Neuronal Plasticity / physiology*
  • Receptors, AMPA / metabolism
  • Retroelements / physiology*
  • Synapses / metabolism*


  • Cacng2 protein, mouse
  • Calcium Channels
  • Receptors, AMPA
  • Retroelements
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2

Associated data

  • PDB/4X3H
  • PDB/4X3I
  • PDB/4X3X