Members of the DAN Family Are BMP Antagonists That Form Highly Stable Noncovalent Dimers

JOURNAL OF MOLECULAR BIOLOGY

卷:424

Article

Kattamuri, Chandramohan¹  Luedeke, David M.¹  Nolan, Kristof¹  Rankin, Scott A.^3,4  Greis, Kenneth D.²  Zorn, Aaron M.^3,4  Thompson, Thomas B.¹ 

[1] Univ Cincinnati, Dept Mol Genet Biochem & Microbiol, Cincinnati, OH 45267 USA

[2] Univ Cincinnati, Dept Canc & Cell Biol, Cincinnati, OH 45267 USA

[3] Cincinnati Childrens Res Fdn, Div Dev Biol, Cincinnati, OH 45229 USA

[4] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45229 USA

关键词: transforming growth factor-beta (TGF-beta);    bone morphogenetic protein (BMP);    BMP antagonist;    DAN family;    protein related to DAN and cerberus (PRDC);   

DOI  :  10.1016/j.jmb.2012.10.003

来源: Elsevier

【 摘 要 】

Signaling of bone morphogenetic protein (BMP) ligands is antagonized by a number of extracellular proteins, including noggin, follistatin and members of the DAN (differential screening selected gene abberative in neuroblastoma) family. Structural studies on the DAN family member sclerostin (a weak BMP antagonist) have previously revealed that the protein is monomeric and consists of an eight-membered cystine knot motif with a fold similar to transforming growth factor-beta ligands. In contrast to sclerostin, certain DAN family antagonists, including protein related to DAN and cerberus (PRDC), have an unpaired cysteine that is thought to function in covalent dimer assembly (analogous to transforming growth factor-beta ligands). Through a combination of biophysical and biochemical studies, we determined that PRDC forms biologically active dimers that potently inhibit BMP ligands. Furthermore, we showed that PRDC dimers, surprisingly, are not covalently linked, as mutation of the unpaired cysteine does not inhibit dimer formation or biological activity. We further demonstrated that the noncovalent PRDC dimers are highly stable under both denaturing and reducing conditions. This study was extended to the founding family member DAN, which also forms noncovalent dimers that are highly stable. These results demonstrate that certain DAN family members can form both monomers and noncovalent dimers, implying that biological activity of DAN family members might be linked to their oligomeric state. Published by Elsevier Ltd.

【 授权许可】

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