@article{8650f5f7552741c0a50854d285f3aadd,
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.",
author = "Wenchi Zhang and Jing Wu and Ward, {Matthew D.} and Sunggu Yang and Chuang, {Yang An} and Meifang Xiao and Ruojing Li and Leahy, {Daniel J.} and Worley, {Paul F.}",
note = "Funding Information: Diffraction data for this study were measured at beamline X29 of the National Synchrotron Light Source with the generous assistance of Annie Heroux. Financial support comes principally from the Offices of Biological and Environmental Research and of Basic Energy Sciences of the U.S. Department of Energy, and from the National Center for Research Resources (P41RR012408) and the National Institute of General Medical Sciences (P41GM103473) of the National Institutes of Health. We thank Alan Long for fluorescence polarization assay and Chris Ross, Daniel Weinberger, and Jeremy Nathans for helpful comments. Thanks to Susumu Tomita (Yale University School of Medicine) and Sabrina S. Burmeister (University of North Carolina) for Stargazin S9D construct and Xenopus tropicalis Arc cDNA clone, respectively. This work was supported by NIMH grant RO1 MH053608 (P.F.W.), NARSAD Young Investigator Grant (J.W.) and Biogen Idec. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",
year = "2015",
month = apr,
day = "22",
doi = "10.1016/j.neuron.2015.03.030",
language = "English (US)",
volume = "86",
pages = "490--500",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "2",
}