title: Structural basis of arc binding to synaptic proteins: implications for cognitive disease.
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.
authors: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Wenchi
authors: W
authors: Zhang
authors: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Jing
authors: J
authors: Wu
authors: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Matthew D
authors: MD
authors: Ward
authors: Department of Nano-Bioengineering, Incheon National University, Incheon, 406-772, Korea.
authors: Sunggu
authors: S
authors: Yang
authors: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Yang-An
authors: YA
authors: Chuang
authors: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Meifang
authors: M
authors: Xiao
authors: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Ruojing
authors: R
authors: Li
authors: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Daniel J
authors: DJ
authors: Leahy
authors: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: pworley@jhmi.edu.
authors: Paul F
authors: PF
authors: Worley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000378:metabolism*; D017781:Genes, Immediate-Early / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009473:Neuronal Plasticity / Q000502:physiology*; D018091:Receptors, AMPA / Q000378:metabolism; D018626:Retroelements / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*
chemical_list: C113940:Cacng2 protein, mouse; D015220:Calcium Channels; D018091:Receptors, AMPA; D018626:Retroelements; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2