Journal Article

PreJuSER-6507

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Oligomer assembly of the C-terminal DISC1 domain (640-854) is controlled by self-association motifs and disease-associated polymorphism S704C

Leliveld, S. R.FZJ* ; Hendriks, P. ; Michel, M. ; Sajnani, G. ; Bader, V. ; Trossbach, S. ; Prikulis, I. ; Hartmann, R.FZJ* ; Jonas, E.FZJ* ; Willbold, D.FZJ* ; Requena, J. R. ; Korth, C.

2009
American Chemical Society Columbus, Ohio

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Please use a persistent id in citations: doi:10.1021/bi900901e

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.

Keyword(s): Animals (MeSH) ; Antibodies, Monoclonal: metabolism (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Nerve Tissue Proteins: chemistry (MeSH) ; Nerve Tissue Proteins: genetics (MeSH) ; Nerve Tissue Proteins: metabolism (MeSH) ; Polymorphism, Genetic (MeSH) ; Protein Multimerization (MeSH) ; Protein Structure, Quaternary (MeSH) ; Protein Structure, Tertiary (MeSH) ; Antibodies, Monoclonal ; DISC1 protein, human ; Nerve Tissue Proteins ; J

Note: Funded by a research grant (LE 2197/1-1) to S.R.L. from the German Research Foundation (DFG) and Stanley Medical Research Institute, Baltimore, MD, to C.K.

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Contributing Institute(s):

1. Strukturbiochemie (ISB-3)

Research Program(s):

1. Funktion und Dysfunktion des Nervensystems (P33)

Appears in the scientific report 2010

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