3-Dimensional structure prediction of C-terminal disrupted in schizophrenia 1: a suspected culprit of schizophrenia

Disrupted in schizophrenia 1 (DISC1) is a scaffolding protein involved in neurogenesis, synaptic development and cell signaling. It acts as a hub protein in different pathways by interacting with multiple proteins and regulates their function it is localized in various subcellular locations, including the nucleus, mitochondria, and cytoskeleton, this 854-amino acid protein comprises two segments: an N-terminal head and a C-terminal coiled-coil region. There are over two hundred interacting partners of DISC1. It is encoded by a gene present on chromosome 1q42.1 and its mutations lead to different genetic defects causing psychiatric conditions. A major genetic defect regarding DISC1 is a translocation event t(1;11) (q42.1;q14.3) which leads to a C-terminal truncated protein residues ∼1-598. This indicates the importance of DISC1 as a therapeutic target but the complete three-dimensional structure of DISC1 is yet not determined only partially reported in complexes or predicted structures are available. To understand the etiology, and pathophysiology of DISC1 the structure of the C-terminus needs to be determined as it participates in major molecular interactions. In this study, different approaches were used to determine the structure of C-terminus DISC1 where threading enabled us to develop a suitable model which was initially refined and later analyzed using quality assessment and validation tools. These findings are a key resource to understand the structural and functional properties of DISC1 and how they can help to identify new therapeutic targets for schizophrenia.