skip to main content

This content will become publicly available on April 9, 2016

Title: Structural Basis of Arc Binding to Synaptic Proteins: Implications for Cognitive Disease

Arc is a cellular immediate-early gene (IEG) that functions at excitatory synapses and is required for learning and memory. Here 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. Finally, 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:
 [1] ;  [1] ;  [2] ;  [3] ;  [1] ;  [1] ;  [4] ;  [2] ;  [1]
  1. Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine, Solomon H. Snyder Dept. of Neuroscience
  2. Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine, Dept. of Biophysics and Biophysical Chemistry
  3. Incheon National Univ. (Korea). Dept. of Nano-Bioengineering
  4. Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine, Dept. of Pharmacology and Molecular Sciences
Publication Date:
OSTI Identifier:
1213728
Grant/Contract Number:
RO1 MH053608
Type:
Accepted Manuscript
Journal Name:
Neuron
Additional Journal Information:
Journal Volume: 86; Journal Issue: 2; Journal ID: ISSN 0896-6273
Publisher:
Cell Press / Elsevier
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES