Tracing the aggregation pathway of the scaffold protein DISC1: Structural implications for chronic mental illnesses.

Disrupted in schizophrenia 1 (DISC1) is a pleiotropic scaffold protein that is postulated to comprise large disordered regions and four distinct structured segments with a high proportion of helical or coiled-coil fold. DISC1 associates with over 300 proteins and is associated with several physiological roles ranging from mitosis to cellular differentiation. Yet, the structural features of the protein are poorly characterized. The C-terminal region (C-region, res. 691-836) forms a tetramer and can also aggregate into amyloid-like fibers, potentially linked to schizophrenia and other chronic mental illnesses. Using a combination of biophysical and structural biology applications, we investigate the structural heterogeneity of three mutants of the C-region, viz., the S713E, S704C and L807-frameshift mutants. We provide evidence for the plasticity of the C region; a thin border separates the conformational flexibility of DISC1 required for interaction with a myriad of partners from disruptive aggregation. Snapshots of aggregates and fibrils growing from a nucleus are presented, along with data supporting the role of the minimal fibrillizing element in the C-region, the β-core. This segment also houses a stretch of residues that is critical for the binding of NDEL1 proteins in the mitotic spindle complex and is absent in the non-binding splice variant DISC1Δ22aa. Physiologically, both the splice variant and the fibers represent loss-of-function states that disrupt cellular division. Our findings highlight the need to decipher the structural elements within the DISC1 C-region to comprehend its physiological role and aggregation-related anomalies, and to establish a rationale for drug development.