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Stabilization of Intrinsically Disordered DKK2 Protein by Fusion to RNA-Binding Domain.


ABSTRACT: Intrinsic disorders are a common feature of hub proteins in eukaryotic interactomes controlling the signaling pathways. The intrinsically disordered proteins (IDPs) are prone to misfolding, and maintaining their functional stability remains a major challenge in validating their therapeutic potentials. Considering that IDPs are highly enriched in RNA-binding proteins (RBPs), here we reasoned and confirmed that IDPs could be stabilized by fusion to RBPs. Dickkopf2 (DKK2), Wnt antagonist and a prototype IDP, was fused with lysyl-tRNA synthetase (LysRS), with or without the fragment crystallizable (Fc) domain of an immunoglobulin and expressed predominantly as a soluble form from a bacterial host. The functional competence was confirmed by in vitro Wnt signaling reporter and tube formation in human umbilical vein endothelial cells (HUVECs) and in vivo Matrigel plug assay. The removal of LysRS by site-specific protease cleavage prompted the insoluble aggregation, confirming that the linkage to RBP chaperones the functional competence of IDPs. While addressing to DKK2 as a key modulator for cancer and ischemic vascular diseases, our results suggest the use of RBPs as stabilizers of disordered proteinaceous materials for acquiring and maintaining the structural stability and functional competence, which would impact the druggability of a variety of IDPs from human proteome.

SUBMITTER: Lee HM 

PROVIDER: S-EPMC6600415 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Stabilization of Intrinsically Disordered DKK2 Protein by Fusion to RNA-Binding Domain.

Lee Hye Min HM   Kwon Soon Bin SB   Son Ahyun A   Kim Doo Hyun DH   Kim Kyun-Hwan KH   Lim Jonghyo J   Kwon Young-Guen YG   Kang Jin Sun JS   Lee Byung Kyu BK   Byun Young Ho YH   Seong Baik L BL  

International journal of molecular sciences 20190611 11


Intrinsic disorders are a common feature of hub proteins in eukaryotic interactomes controlling the signaling pathways. The intrinsically disordered proteins (IDPs) are prone to misfolding, and maintaining their functional stability remains a major challenge in validating their therapeutic potentials. Considering that IDPs are highly enriched in RNA-binding proteins (RBPs), here we reasoned and confirmed that IDPs could be stabilized by fusion to RBPs. Dickkopf2 (DKK2), Wnt antagonist and a prot  ...[more]

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