Structure of protein related to DAN and Cerberus (PRDC): Insights into the mechanism of BMP antagonism
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Authors
Nolan, K.
Kattamuri, C.
Luedeke, D.M.
Deng, A.
Jagpal, A.
Zhang, F.
Linhardt, Robert J.
Kenny, A.P.
Zorn, A.M.
Thompson, T.B.
Issue Date
2013
Type
Article
Language
ENG
Keywords
Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
Alternative Title
Abstract
The Bone Morphogenetic Proteins (BMP) are secreted ligands largely known for their functional roles in embryogenesis and tissue development. A number of structurally diverse extracellular antagonists inhibit BMP ligands to regulate signaling. The DAN family of antagonists represents the largest group of BMP inhibitors, however, little is known for how they mechanistically inhibit BMP ligands. Here, we present the structure of the DAN family member Protein Related to Dan and Cerberus (PRDC) solved by X-ray crystallography. The structure reveals an unexpected growth factor-like appearance with a novel dimerization mechanism that is formed through extensive β-strand contacts. Using site-directed mutagenesis coupled with in vitro and in vivo activity assays, we identified a BMP binding epitope on PRDC. We also determined that PRDC binds heparin with high affinity and that heparin binding to PRDC interferes with BMP antagonism. These results offer insight for how DAN family antagonists functionally inhibit BMP ligands.
Description
Structure, 21, 1417–1429
Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
Full Citation
Structure of protein related to DAN and Cerberus (PRDC): Insights into the mechanism of BMP antagonism, K. Nolan, C. Kattamuri, D.M. Luedeke, A. Deng, A. Jagpal, F. Zhang, R. J. Linhardt, A. P. Kenny, A. M. Zorn, T. B. Thompson, Structure, 21, 1417–1429, 2013.
Publisher
Elsevier