%0 Journal Article
%A Leliveld, S. R.
%A Hendriks, P.
%A Michel, M.
%A Sajnani, G.
%A Bader, V.
%A Trossbach, S.
%A Prikulis, I.
%A Hartmann, R.
%A Jonas, E.
%A Willbold, D.
%A Requena, J. R.
%A Korth, C.
%T Oligomer assembly of the C-terminal DISC1 domain (640-854) is controlled by self-association motifs and disease-associated polymorphism S704C
%J Biochemistry
%V 48
%@ 0006-2960
%C Columbus, Ohio
%I American Chemical Society
%M PreJuSER-6507
%P 7746 - 7755
%D 2009
%Z 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.
%X 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.
%K Animals
%K Antibodies, Monoclonal: metabolism
%K Humans
%K Mice
%K Nerve Tissue Proteins: chemistry
%K Nerve Tissue Proteins: genetics
%K Nerve Tissue Proteins: metabolism
%K Polymorphism, Genetic
%K Protein Multimerization
%K Protein Structure, Quaternary
%K Protein Structure, Tertiary
%K Antibodies, Monoclonal (NLM Chemicals)
%K DISC1 protein, human (NLM Chemicals)
%K Nerve Tissue Proteins (NLM Chemicals)
%K J (WoSType)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:19583211
%U <Go to ISI:>//WOS:000268720300021
%R 10.1021/bi900901e
%U https://juser.fz-juelich.de/record/6507