期刊
NEURON
卷 86, 期 2, 页码 490-500出版社
CELL PRESS
DOI: 10.1016/j.neuron.2015.03.030
关键词
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资金
- Office of Biological and Environmental Research of the U.S. Department of Energy
- Office of Basic Energy Sciences of the U.S. Department of Energy
- National Center for Research Resources [P41RR012408]
- National Institute of General Medical Sciences of the National Institutes of Health [P41GM103473]
- NIMH [RO1 MH053608]
- NARSAD
- Biogen Idec.
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 TARP gamma 2 (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.
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