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J Biol Chem. 2017 Apr 21;292(16):6468-6477. doi: 10.1074/jbc.M116.773903. Epub 2017 Mar 1.

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.

Author information

1
From the Department of Neuropathology and.
2
the Integrated Structural Biology Grenoble (ISBG) CNRS, CEA, Université Grenoble Alpes, EMBL, 38042 Grenoble, France.
3
the Institute of Physical Biology, Heinrich Heine University, 40225 Düsseldorf, Germany.
4
the MRC Human Genetics Unit, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
5
the Institute of Complex Systems (ICS-6: Structural Biochemistry), Forschungszentrum Jülich, 52425 Jülich, Germany, and.
6
From the Department of Neuropathology and nicholas.bradshaw@hhu.de.
7
From the Department of Neuropathology and ckorth@hhu.de.

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.

KEYWORDS:

DISC1; ESPRIT; analytical ultracentrifugation; circular dichroism (CD); domain structure; mental illness; protein solubility; protein stability; recombinant protein expression; schizophrenia

PMID:
28249940
PMCID:
PMC5399101
DOI:
10.1074/jbc.M116.773903
[Indexed for MEDLINE]
Free PMC Article

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