Specialized iNANO lecture: The capsid domain of Arc changes its oligomerization propensity through direct interaction with the NMDA receptor

Associate professor Kaare Teilum, Section for Biomolecular Sciences, Department of Biology, University of Copenhagen

The capsid domain of Arc changes its oligomerization propensity through direct interaction with the NMDA receptor 

The Activity-regulated cytoskeleton-associated protein, Arc, is highly expressed in neuronal dendrites and is involved in synaptic scaling and synaptic plasticity as a component in the systems that drives internalization of AMPA and NMDA receptors.

Arc, which is homologues to the capsid forming Gag proteins from the retrotransposon Ty3/Gypsy family, was recently shown capable to form capsids that can encapsulate Arc’s own mRNA and transport it to neighbouring neurons for transcription. However, the molecular events that lead to formation of Arc capsids and thus how the process is regulated are not known. Here we show that the capsid domain of Arc has a rigid structure that can be stimulated to transiently form homogeneous oligomers with a similar size as the capsids formed by full length Arc. This process is efficiently suppressed by interactions with the GluN2A and the GluN2B NMDA receptor subunits.

Using NMR spectroscopy, we determined the solution structure of the monomeric Arc capsid domain and mapped the dynamics of the structure. In contrast to the capsid forming Gag protein from HIV where structural flexibility is important for capsid formation, the structure of Arc is very rigid. We show by negative stain EM and DLS that the oligomeric structures formed by the capsid domain are not as stable as the capsids formed by full length Arc. Still, our results show that the capsid domain alone serves as good model for the initial steps in oligomerization of Arc. We demonstrate how ligand binding modulate the oligomerization propensity and thus suggests that Arc’s ability to transfer mRNA between cells may be controlled by the lack of stabilizing ligands as GluN2A and GluN2B. Our work also lays the foundation for a detailed molecular understanding of the function of Arc and other domesticated retroviral protein in the human genome.

Host: Associate professor Frans Mulder, iNANO & Dept. of Chemistry, Aarhus University