ID | 52403 |
JaLCDOI | |
FullText URL | |
Author |
Fujii, Yasuyuki
Hoshino, Tyuji
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Abstract | Dickkopf (DKK) proteins interact with low-density lipoprotein receptor-related protein 5/6 (LRP5/6) to modulate WNT signaling. The interaction is mediated by a cysteine-rich domain (C2) in the DKK protein and β-propeller domains (PD) of LRP5/6. However, the third member of the DKK family (DKK3) does not bind to LRP5/6. To determine why DKK3 does not bind to the receptor domains, we performed a molecular modeling simulation study including homology modeling, protein-protein docking and molecular dynamics (MD). The computed affinities (ΔGbinding) between the C2 and PD models were consistent with the previously reported experimental results. The C2 model of DKK3 showed the lowest affinity for PD models. Multiple sequence alignment of C2 domains revealed that the DKK3 genes have a unique 7-amino-acid insertion (L249-E255 in human DKK3) and P258 in a finger loop 1 (FL1). Interestingly, the insertion sequence is evolutionally conserved. MD simulations of high-affinity complex models of C2 and PD showed that FL1 directly interacts with the PD models and stabilizes the complex models. We also built a 7-amino-acid-deletion/P258G mutant model of DKK3C2 and estimated its affinities for the PD models. The affinity for human LRP5PD2 was increased by the substitution
(ΔGbinding=-48.9kcal/mol) and the affinity was compatible with that of high-affinity ligands. The results suggested that the lack of affinity between human DKK3 and human LRP5/6 results from:
i) insertion of the 7 amino acids, and ii) P258 in human DKK3. The sequence differences thus suggest an explanation for this unique property of DKK3.
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Keywords | DKK3
molecular modeling
protein-protein docking
LRP5/6
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Amo Type | Original Article
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Publication Title |
Acta Medica Okayama
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Published Date | 2014-04
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Volume | volume68
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Issue | issue2
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Publisher | Okayama University Medical School
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Start Page | 63
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End Page | 78
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ISSN | 0386-300X
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NCID | AA00508441
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Content Type |
Journal Article
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language |
English
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Copyright Holders | CopyrightⒸ 2014 by Okayama University Medical School
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File Version | publisher
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Refereed |
True
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PubMed ID | |
Web of Science KeyUT |