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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred


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Volume 394, Issue 11

Issues

Revisiting Disrupted-in-Schizophrenia 1 as a scaffold protein

Antony S.K. Yerabham
  • Department of Neuropathology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Oliver H. Weiergräber
  • Institute of Complex Systems (ICS-6: Structural Biochemistry), Forschungszentrum Jülich, D-52425 Jülich, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Nicholas J. Bradshaw
  • Corresponding author
  • Department of Neuropathology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Carsten Korth
  • Corresponding author
  • Department of Neuropathology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2013-07-05 | DOI: https://doi.org/10.1515/hsz-2013-0178

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.

Keywords: DISC1; mental illness; protein-protein interactions; signaling pathways; structure; threading models

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About the article

Antony S.K. Yerabham

Antony Sravan Kumar Yerabham completed his Master’s degree at the University of Hyderabad, India in the year 2010. Following this, he received training in Macromolecular Crystallography as a Project Junior Research Fellow in Dr. Rajan Sankaranarayanan’s group at the Centre for Cellular and Molecular Biology, Hyderabad. Currently he is pursuing his Doctoral studies on the structure and function of the DISC1 protein and its interaction partners, in the work group of Prof. Dr. Carsten Korth, at the Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.

Nicholas J. Bradshaw

Nicholas Bradshaw received his BSc in Natural Sciences (Biology with Physics) from Durham University in 2005 and undertook his doctorate at the University of Edinburgh under the supervision of Dr Kirsty Millar and Prof David Porteous on the interactions of the schizophrenia-related proteins DISC1 and NDE1. After receiving his PhD in 2009, Nick continued his research into the biochemical and biophysical properties of these and related proteins pertinent to major mental health in Edinburgh. In 2011 he received a postdoctoral fellowship from the Alexander von Humboldt Foundation to further develop his research in the laboratory of Prof Dr Carsten Korth at the Heinrich Heine University, Düsseldorf.

Carsten Korth

Carsten Korth did his MD at the LMU Munich and PhD at the VU Amsterdam. After a residency in psychiatry at the Max Planck Institute for Psychiatry, he moved to fundamental research in protein conformational disease, first to the University of Zurich where he also co-founded the company Prionics, then to the Institute for Neurodegenerative Diseases, University of California San Francisco (Prof Stanley Prusiner). Since 2002 he is indepdendent investigator at the Heinrich Heine University of Düsseldorf focussing on protein pathology in brain diseases, particularly chronic mental illnesses like schizophrenia or recurrent affective disorders.


Corresponding authors: Nicholas J. Bradshaw and Carsten Korth, Department of Neuropathology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany, e-mail: ;


Received: 2013-05-14

Accepted: 2013-07-03

Published Online: 2013-07-05

Published in Print: 2013-11-01


Citation Information: Biological Chemistry, Volume 394, Issue 11, Pages 1425–1437, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2013-0178.

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