This title appears in the Scientific Report :
2010
Please use the identifier:
http://dx.doi.org/10.1021/bi900901e in citations.
Oligomer assembly of the C-terminal DISC1 domain (640-854) is controlled by self-association motifs and disease-associated polymorphism S704C
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 middl...
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Personal Name(s): | Leliveld, S. R. |
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Hendriks, P. / Michel, M. / Sajnani, G. / Bader, V. / Trossbach, S. / Prikulis, I. / Hartmann, R. / Jonas, E. / Willbold, D. / Requena, J. R. / Korth, C. | |
Contributing Institute: |
Strukturbiochemie; ISB-3 |
Published in: | Biochemistry, 48 (2009) S. 7746 - 7755 |
Imprint: |
Columbus, Ohio
American Chemical Society
2009
|
Physical Description: |
7746 - 7755 |
PubMed ID: |
19583211 |
DOI: |
10.1021/bi900901e |
Document Type: |
Journal Article |
Research Program: |
Funktion und Dysfunktion des Nervensystems |
Series Title: |
Biochemistry
48 |
Subject (ZB): | |
Publikationsportal JuSER |
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. |