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

Abstract

SUMMARY 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.

Metabotropic Glutamate Receptors Induce a Form of LTP Controlled by Translation and Arc Signaling in the Hippocampus

“…Hippocampal slices (400 m) were prepared as described previously (Yang et al, 2013) in ice-cold dissection buffer containing the following: 212.7 mM sucrose, 2.6 mM KCl, 1.23 mM NaH 2 PO 4 , 26 mM NaHCO 3 , 10 mM dextrose, 3 mM MgCl 2 , and 1 mM CaCl 2 bubbled with a mixture of 5% CO 2 and 95% O 2 . For recordings in aged rats, we used transcardial perfusion before isolating the brain (Yang et al, 2013). All the procedures were approved by the Johns Hopkins University animal care committee.…”

“…High-frequency tetanus consisted of four 200 Hz epochs (0.5 s) delivered at 0.2 Hz in the presence of an NMDA receptor antagonist (100 M D,L-APV). Under our experimental conditions, this protocol induces robust LTP in Long-Evans rats in both CA1 (Boric et al, 2008) and CA3 synapses (Yang et al, 2013). Theta burst stimulation (TBS) consisted of 4 or 6 theta epochs delivered at 0.1 Hz.…”

“…It is well established that stimulation of Type I mGluRs (mGluR1 and mGluR5) alone can induce LTD expressed as endocytosis of synaptic AMPA receptors (Lüscher and Huber, 2010). Mechanistically, this mGluR-dependent form of LTD (mGluR-LTD) and NMDAR-LTD are widely different.…”

“…Mechanistically, this mGluR-dependent form of LTD (mGluR-LTD) and NMDAR-LTD are widely different. They can operate on different subunits of the AMPA receptor (Casimiro et al, 2011); and while the induction of mGluR-LTD requires intact protein synthesis and it is under the control of Arc/arg3.1 signaling, the induction of NMDAR-LTD does not (Huber et al, 2000;Park et al, 2008;Waung et al, 2008). Importantly, the dysregulation of mGluR-LTD has clear functional consequences as it has been implicated in learning deficits associated with aging (Lee et al, 2005;Boric et al, 2008;Yang et al, 2013), as well as in neuropathological conditions, including fragile X mental retardation (Huber et al, 2002;Bear et al, 2004) and Alzheimer's disease (Hsieh et al, 2006).…”

Going Retro: Ancient Viral Origins of Cognition

“…The possibility that Arc, an absolutely indispensable component of learning and memory, has retroviral origins was surprising and intriguing. New support for this hypothesis comes in this issue, where Zhang et al (2015) report the first crystal structure of an Arc domain.…”