Revisiting Disrupted-in-Schizophrenia 1 as a scaffold protein

Abstract

Disrupted-in-Schizophrenia 1 (DISC1) is a widely-accepted genetic risk factor for schizophrenia and many other major mental illnesses. Traditionally DISC1 has been referred to as a 'scaffold protein' because of its ability to bind to a wide array of other proteins, including those of importance for neurodevelopment. Here, we review the characteristic properties shared between established scaffold proteins and DISC1. We find DISC1 to have many, but not all, of the characteristics of a scaffold protein, as it affects a considerable number of different, but related, signaling pathways, in most cases through inhibition of key enzymes. Using threading algorithms, the C-terminal portion of DISC1 could be mapped to extended helical structures, yet it may not closely resemble any of the known tertiary folds. While not completely fitting the classification of a classical scaffold protein, DISC1 does appear to be a tightly regulated and multi-faceted inhibitor of a wide range of enzymes from interrelated signaling cascades (Diverse Inhibitor of Signaling Cascades), which together contribute to neurodevelopment and synaptic homeostasis. Consequently, disruption of this complex regulation would be expected to lead to the range of major mental illnesses in which the DISC1 gene has been implicated.

A structural organization for the Disrupted in Schizophrenia 1 protein, identified by high-throughput screening, reveals distinctly folded regions, which are bisected by mental illness-related mutations

“…These constructs represented compactly folded domains with hydrophobic cores, with similar variants having only small unstructured terminal extensions. In contrast, and reflecting the nature of DISC1 as a primarily helical scaffold protein (5,8), this screen, when coupled to purification and biophysical analysis, instead identified four helical regions within DISC1 as being both soluble and structured. We have defined these as the D, I, S, and C regions and propose them to represent distinct, structured regions of the human DISC1 protein, which coincide with established binding sites for several of the key protein interaction partners of DISC1 (Fig.…”

Proteomic Characterization of the Brain and Cerebrospinal Fluid of Schizophrenia Patients

“…As discussed previously in the present chapter, DISC1 has been considered a genetic risk factor for schizophrenia and also for other disorders [82]. Recently, molecular studies have demonstrated that DISC1 may act as a scaffold protein for complexes involved in neurite outgrowth and function.…”

“…GSK-3β is a serine/threonine protein kinase involved in the Wnt signaling cascade, the PI3K cascade and the mitogen-activated protein kinase cascade. Microtubule-associated proteins (MAP) are phosphorylated by GSK-3β, and impairment of this cascade may lead to structural abnormalities observed in schizophrenia [82][83][84]. PDE4 is a cAMP-specific PDE with high affinity for cAMP and protein kinase A (PKA).…”

Deficits in axon‐associated proteins in prefrontal white matter in bipolar disorder but not schizophrenia

“…In addition, analysis of genomic, transcriptomic and protein interaction data has revealed enrichment of cytoskeletal networks in BD , suggestive of a general alteration in cytoskeleton dynamics in this disorder. DISC1 is a multifunctional protein that plays a role in regulating a large number of signaling pathways involved in brain development and function . Protein expression of a 75kDa DISC1 isoform was unchanged in the orbitofrontal cortex in BD , although this isoform showed increased nuclear and decreased cytoplasmic localization in cultured neuronal precursor cells obtained from subjects with BD .…”