Protein aggregation resulting from disruptions in proteostasis in the brains of patients with chronic mental illness is an emerging theme particularly in the study of schizophrenia. For example, proteins such as Disrupted in Schizophrenia 1 (DISC1) and dysbindin-1B are present in insoluble aggregates, detectable within brain homogenates from such patients. Using an epitope discovery and proteomics approach to compare post-mortem brain samples from schizophrenia patients and controls, we recently identified TRIO-Binding Protein 1 (TRIOBP-1, also known as Tara) as another aggregation-associated protein. We hypothesized that TRIOBP-1 aggregation likely arises from a specific subcellular process, and therefore that it should be possible to identify regions of the TRIOBP-1 protein that are essential for its aggregation. Here, we probed the domain organization of TRIOBP-1, via solubility and stability testing of recombinant protein fragments, and found that it possesses two distinct coiled-coil domains: the central and C-terminal domains. The central domain inhibited the de-polymerization of F-actin and was also responsible for TRIOBP-1 oligomerization and, along with an N-terminal Pleckstrin homology domain, affected neurite outgrowth. In neuroblastoma cells, the aggregation propensity of TRIOBP-1 arose from its central domain, and a short linker region, narrowed to within amino acids 324-348, between its first two coiled-coils was identified as being essential for TRIOBP-1 aggregate formation. We conclude that TRIOBP-1 appears to aggregate via one or more cellular mechanisms, which have the potential to be of physiological relevance for the biological processes underlying the development of chronic mental illness.
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