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Structural basis of arc binding to synaptic proteins: implications for cognitive disease
Wenchi Zhang1, Jing Wu1, Matthew D Ward2
1Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Neuron
|April 14, 2015
Summary
Arc, a gene crucial for learning and memory, shares structural similarities with HIV. Its unique binding pocket is key to synaptic function and may be a target for new drugs.
Area of Science:
- Neuroscience
- Molecular Biology
- Evolutionary Biology
Background:
- Arc is a cellular immediate-early gene (IEG) vital for synaptic plasticity, learning, and memory.
- Its precise molecular mechanisms and evolutionary origins have remained largely unelucidated.
Purpose of the Study:
- To determine the structural basis of Arc function at excitatory synapses.
- To investigate the evolutionary origins of Arc and its role in neural plasticity.
- To explore the potential for therapeutic targeting of Arc.
Main Methods:
- X-ray crystallography to resolve Arc subdomain structures.
- Biochemical assays to identify Arc-binding partners.
- Analysis of evolutionary relationships with retrotransposons.
Main Results:
- Arc exhibits a bi-lobar architecture homologous to the HIV gag capsid domain.
- Arc originated from a retrotransposon, domesticated for synaptic functions in vertebrates.
- A unique N-terminal hydrophobic pocket mediates binding to synaptic proteins like TARPγ2 and CaMKII.
- Identified novel Arc-binding partners, including genes linked to schizophrenia.
- Small molecules were found to inhibit Arc N-lobe binding.
Conclusions:
- Arc's structure reveals an ancient evolutionary origin from retrotransposons.
- The N-terminal lobe's binding pocket is critical for Arc's synaptic roles.
- Arc's synaptic function is potentially druggable, offering therapeutic avenues for neurological disorders and schizophrenia.
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