Oligomer Assembly of the C-Terminal DISC1 Domain (640−854) Is Controlled by Self-Association Motifs and Disease-Associated Polymorphism S704C
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- 作者：S. Rutger Leliveld ; Philipp Hendriks ; Max Michel ; Gustavo Sajnani ; Verian Bader ; Svenja Trossbach ; Ingrid Prikulis ; Rudolf Hartmann ; Esther Jonas ; Dieter Willbold ; Jess R. Requena ; Carsten Korth
- 刊名：Biochemistry
- 出版年：2009
- 出版时间：August 18, 2009
- 年：2009
- 卷：48
- 期：32
- 页码：7746-7755
- 全文大小：960K
- 年卷期：v.48,no.32(August 18, 2009)
- ISSN：1520-4995
文摘
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.