Oligomer Assembly of the C-Terminal DISC1 Domain (640−854) Is Controlled by Self-Association Motifs and Disease-Associated Polymorphism S704C

Genetic studies have established a role of disrupted-in-schizophrenia-1 (DISC1) in chronic mental diseases (CMD). Limited experimental data are available on the domain structure of the DISC1 protein although multiple interaction partners are known including a self-association domain within the middle part of DISC1 (residues 403−504). The DISC1 C-terminal domain is deleted in the original Scottish pedigree where DISC1 harbors two coiled-coil domains and disease-associated polymorphisms at 607 and 704, as well as the important nuclear distribution element-like 1 (NDEL1) binding site at residues 802−839. Here, we performed mutagenesis studies of the C-terminal domain of the DISC1 protein (residues 640−854) and analyzed the expressed constructs by biochemical and biophysical methods. We identified novel DISC1 self-association motifs and the necessity of their concerted action for orderly assembly: the region 765−854 comprising a coiled-coil domain is a dimerization domain and the region 668−747 an oligomeriza...