title: Oligomer assembly of the C-terminal DISC1 domain (640-854) is controlled by self-association motifs and disease-associated polymorphism S704C.
abstract: 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 oligomerization domain; dimerization was found to be a prerequisite for orderly assembly of oligomers. Consistent with this, disease-associated polymorphism C704 displayed a slightly higher oligomerization propensity. The heterogeneity of DISC1 multimers in vitro was confirmed with a monoclonal antibody binding exclusively to HMW multimers. We also identified C-terminal DISC1 fragments in human brains, suggesting that C-terminal fragments could carry out DISC1-dependent functions. When the DISC1 C-terminal domain was transiently expressed in cells, it assembled into a range of soluble and insoluble multimers with distinct fractions selectively binding NDEL1, indicating functionality. Our results suggest that assembly of the C-terminal domain is controlled by distinct domains including the disease-associated polymorphism 704 and is functional in vivo.
authors: Department of Neuropathology, Heinrich-Heine University Dusseldorf, 40225 Dusseldorf, Germany.
authors: S Rutger
authors: SR
authors: Leliveld
authors: Philipp
authors: P
authors: Hendriks
authors: Max
authors: M
authors: Michel
authors: Gustavo
authors: G
authors: Sajnani
authors: Verian
authors: V
authors: Bader
authors: Svenja
authors: S
authors: Trossbach
authors: Ingrid
authors: I
authors: Prikulis
authors: Rudolf
authors: R
authors: Hartmann
authors: Esther
authors: E
authors: Jonas
authors: Dieter
authors: D
authors: Willbold
authors: Jesús R
authors: JR
authors: Requena
authors: Carsten
authors: C
authors: Korth
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary
chemical_list: D000911:Antibodies, Monoclonal; C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins