Members of the DAN family are BMP antagonists that form highly stable noncovalent dimers.
Members of the DAN family are BMP antagonists that form highly stable noncovalent dimers.
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DOI：
10.1016/j.jmb.2012.10.003
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发表时间：
2012-12-14
影响因子：
5.6
通讯作者：
Thompson, Thomas B.
中科院分区：
文献类型：
--
作者：
Kattamuri, Chandramohan;Luedeke, David M.;Nolan, Kristof;Rankin, Scott A.;Greis, Kenneth D.;Zorn, Aaron M.;Thompson, Thomas B.
关键词：
BMP配体的信号转导被许多细胞外蛋白所拮抗，包括noggin、Folistatin和DAN家族成员。先前对DAN家族成员硬化素(一种弱的骨形态发生蛋白拮抗剂)的结构研究表明，该蛋白是单体，由8个成员的半胱氨酸结基序组成，其折叠类似于转化生长因子-β配体。与硬化蛋白不同的是，某些DAN家族拮抗剂，包括与DAN和Cerberus相关的蛋白(PrDC)，具有不成对的半胱氨酸，被认为是在共价二聚体组装中发挥作用(类似于转化生长因子-β配体)。通过生物物理和生化研究的结合，我们确定PRDC形成具有生物活性的二聚体，能够有效地抑制BMP配体。此外，我们发现，令人惊讶的是，PRDC二聚体并不是共价连接的，因为未配对的半胱氨酸的突变不会抑制二聚体的形成或生物活性。我们进一步证明了非共价的PRDC二聚体在变性和还原条件下都是高度稳定的。这项研究扩展到了创始家族成员丹，它也形成了高度稳定的非共价二聚体。这些结果表明，某些DAN家族成员既可以形成单体，也可以形成非共价二聚体，这意味着DAN家族成员的生物活性可能与他们的低聚状态有关。
Signaling of BMP ligands is antagonized by a number of extracellular proteins, including noggin, follistatin and members of the DAN 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 8-membered cystine knot motif with a fold similar to TGF-β 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 TGF-β 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.
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影响因子：
64.8
作者：
Bouwmeester, T;Kim, SH;DeRobertis, EM
通讯作者：
DeRobertis, EM
影响因子：
11.4
作者：
Cash, Jennifer N.;Rejon, Carlis A.;Thompson, Thomas B.
通讯作者：
Thompson, Thomas B.
影响因子：
4.8
作者：
Cash, Jennifer N.;Angerman, Elizabeth B.;Thompson, Thomas B.
通讯作者：
Thompson, Thomas B.
DOI：
10.1038/nsb766
发表时间：
2002-03-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Hart, PJ;Deep, S;Hinck, AP
通讯作者：
Hinck, AP
影响因子：
4
作者：
Hogan, BLM
通讯作者：
Hogan, BLM