The DAN (differential screening-selected gene aberrative in neuroblastoma) family are a group of secreted extracellular proteins which typically bind to and antagonize BMP (bone morphogenetic protein) ligands. Previous studies have revealed discrepancies between the oligomerization state of certain DAN family members, with SOST (a poor antagonist of BMP signaling) forming a monomer while Grem1, Grem2, and NBL1 (more potent BMP antagonists) form non-disulfide linked dimers. The protein SOSTDC1 (Sclerostin domain containing protein 1) is sequentially similar to SOST, but has been shown to be a better BMP inhibitor. In order to determine the oligomerization state of SOSTDC1 and determine what effect dimerization might have on the mechanism of DAN family antagonism of BMP signaling, we isolated the SOSTDC1 protein and, using a battery of biophysical, biochemical, and structural techniques, showed that SOSTDC1 forms a highly stable non-covalent dimer. Additionally, this SOSTDC1 dimer was shown, using an in vitro cell based assay system, to be an inhibitor of multiple BMP signaling growth factors, including GDF5, while monomeric SOST was a very poor antagonist. These results demonstrate that SOSTDC1 is distinct from paralogue SOST in terms of both oligomerization and strength of BMP inhibition.

中文翻译：

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DAN家族拮抗剂SOSTDC1和SOST的不同低聚状态的表征。

DAN（神经母细胞瘤中差异筛选选择的基因异常）家族是一组分泌的细胞外蛋白，通常结合并拮抗BMP（骨形态发生蛋白）配体。先前的研究表明某些DAN家族成员的低聚状态之间存在差异，SOST（BMP信号的弱拮抗剂）形成单体，而Grem1，Grem2和NBL1（更有效的BMP拮抗剂）形成非二硫键连接的二聚体。蛋白质SOSTDC1（含有硬化蛋白结构域的蛋白质1）顺序类似于SOST，但已被证明是更好的BMP抑制剂。为了确定SOSTDC1的低聚状态并确定二聚化可能对BMP信号的DAN家族拮抗作用产生什么影响，我们分离了SOSTDC1蛋白，并使用一系列生物物理方法，生化和结构技术表明，SOSTDC1形成高度稳定的非共价二聚体。此外，使用基于体外细胞的测定系统，该SOSTDC1二聚体显示是多种BMP信号生长因子（包括GDF5）的抑制剂，而单体SOST是非常差的拮抗剂。这些结果表明，SOSTDC1在寡聚化和BMP抑制强度方面均与旁系同源SOST不同。