ArticleThe Journal of biological chemistry2017
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.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 25 citations in OpenAlex.
- The schizophrenia associated protein DISC1 forms a multivalent tetrameric hub via conserved UVR dimers.Nature communications · 2026Article
- Protein aggregation identified in olfactory neuronal cells is associated with cognitive impairments in a subset of living schizophrenia patients.Molecular psychiatry · 2025Article
- Tracing the aggregation pathway of the scaffold protein DISC1: Structural implications for chronic mental illnesses.Journal of structural biology: X · 2025Article
- Mapping the Domain Structure and Aggregation Propensity of Proteins Using a Gateway Plasmid Vector System.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Evidence of DISC1 as an arsenic binding protein and implications regarding its role as a translational activator.Frontiers in molecular biosciences · 2023Article
- Protein Misfolding and Aggregation in the Brain: Common Pathogenetic Pathways in Neurodegenerative and Mental Disorders.International journal of molecular sciences · 2022Review
- Conformational heterogeneity coupled with β-fibril formation of a scaffold protein involved in chronic mental illnesses.Translational psychiatry · 2021Article
- Disorder Mediated Oligomerization ofThe journal of physical chemistry. B · 2019Article
- Protein misassembly and aggregation as potential convergence points for non-genetic causes of chronic mental illness.Molecular psychiatry · 2019Review
- Mechanisms underlying the role of DISC1 in synaptic plasticity.The Journal of physiology · 2018Review
- Using mouse transgenic and human stem cell technologies to model genetic mutations associated with schizophrenia and autism.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2018Review
- Quantitative Proteomics of Synaptosomal Fractions in a Rat Overexpressing Human DISC1 Gene Indicates Profound Synaptic Dysregulation in the Dorsal Striatum.Frontiers in molecular neuroscience · 2018Article
- Biophysical insights from a single chain camelid antibody directed against the Disrupted-in-Schizophrenia 1 protein.PloS one · 2018Article
- Transfer of disrupted-in-schizophrenia 1 aggregates between neuronal-like cells occurs in tunnelling nanotubes and is promoted by dopamine.Open biology · 2017Article
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Authors and funding
10 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Disrupted in Schizophrenia 1 (DISC1) is a scaffolding protein of significant importance for neurodevelopment and a prominent candidate protein in the pathology of major mental illness. DISC1 modulates a number of critical neuronal signaling pathways through protein-protein interactions; however, the mechanism by which this occurs and how DISC1 causes mental illness is unclear, partly because knowledge of the structure of DISC1 is lacking. A lack of homology with known proteins has hindered attempts to define its domain composition. Here, we employed the high-throughput Expression of Soluble Proteins by Random Incremental Truncation (ESPRIT) technique to identify discretely folded regions of human DISC1 via solubility assessment of tens of thousands of fragments of recombinant DISC1. We identified four novel structured regions, named D, I, S, and C, at amino acids 257-383, 539-655, 635-738, and 691-836, respectively. One region (D) is located in a DISC1 section previously predicted to be unstructured. All regions encompass coiled-coil or α-helical structures, and three are involved in DISC1 oligomerization. Crucially, three of these domains would be lost or disrupted by a chromosomal translocation event after amino acid 597, which has been strongly linked to major mental illness. Furthermore, we observed that a known illness-related frameshift mutation after amino acid 807 causes the C region to form aberrantly multimeric and aggregated complexes with an unstable secondary structure. This newly revealed domain architecture of DISC1, therefore, provides a powerful framework for understanding the critical role of this protein in a variety of devastating mental illnesses.
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