Analysis of the Interaction and Functional Determinants of Arc and Its Regulation of Dynamin




Byers, Christopher Eugene

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Recent evidence indicates that the activity-regulated cytoskeleton-associated protein, Arc, facilitates endocytosis of glutamate receptors and regulates cytoskeletal organization in neuronal dendrites. Both of these functions may be mediated by its reported interaction with dynamin 2, a large (~100 kDa) GTPase that participates in receptor-mediated endocytosis, actin polymerization, and microtubule stabilization. The effects of Arc on dynamin activities have not been characterized. Therefore, I have purified bacterially-expressed Arc and have shown that it enhances dynamin 2, and the neuronal and testes expressed dynamin 3, self-assembly in vitro and stimulates their GTPase activity. However, Arc interacts with dynamin 1, the neuronal isoform required for rapid pre-synaptic vesicle recycling, but does not stimulate its activity or assembly. The Arc-dynamin interaction is strongly dependent on ionic strength and the polymerization state of dynamin, which Arc enhances. Consequently, biophysical studies were used to confirm Arc is capable of forming higher order oligomers. Contrary to published findings, binding studies show Arc interacts with the proline-rich domain of dynamin and not the pleckstrin homology domain. All together, these results provide a mechanism to explain the previously reported role of Arc in glutamate receptor internalization.

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