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@ARTICLE{Leliveld:6507,
author = {Leliveld, S. R. and Hendriks, P. and Michel, M. and
Sajnani, G. and Bader, V. and Trossbach, S. and Prikulis, I.
and Hartmann, R. and Jonas, E. and Willbold, D. and Requena,
J. R. and Korth, C.},
title = {{O}ligomer assembly of the {C}-terminal {DISC}1 domain
(640-854) is controlled by self-association motifs and
disease-associated polymorphism {S}704{C}},
journal = {Biochemistry},
volume = {48},
issn = {0006-2960},
address = {Columbus, Ohio},
publisher = {American Chemical Society},
reportid = {PreJuSER-6507},
pages = {7746 - 7755},
year = {2009},
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.},
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.},
keywords = {Animals / Antibodies, Monoclonal: metabolism / Humans /
Mice / Nerve Tissue Proteins: chemistry / Nerve Tissue
Proteins: genetics / Nerve Tissue Proteins: metabolism /
Polymorphism, Genetic / Protein Multimerization / Protein
Structure, Quaternary / Protein Structure, Tertiary /
Antibodies, Monoclonal (NLM Chemicals) / DISC1 protein,
human (NLM Chemicals) / Nerve Tissue Proteins (NLM
Chemicals) / J (WoSType)},
cin = {ISB-3},
ddc = {570},
cid = {I:(DE-Juel1)VDB942},
pnm = {Funktion und Dysfunktion des Nervensystems},
pid = {G:(DE-Juel1)FUEK409},
shelfmark = {Biochemistry $\&$ Molecular Biology},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:19583211},
UT = {WOS:000268720300021},
doi = {10.1021/bi900901e},
url = {https://juser.fz-juelich.de/record/6507},
}