Veverka Vaclav, Henry Alistair J, Slocombe Patrick M, Ventom Andrew, Mulloy Barbara, Muskett Frederick W, Muzylak Mariusz, Greenslade Kevin, Moore Adrian, Zhang Li, Gong Jianhua, Qian Xueming, Paszty Chris, Taylor Richard J, Robinson Martyn K, Carr Mark D
Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom.
J Biol Chem. 2009 Apr 17;284(16):10890-900. doi: 10.1074/jbc.M807994200. Epub 2009 Feb 10.
The secreted glycoprotein sclerostin has recently emerged as a key negative regulator of Wnt signaling in bone and has stimulated considerable interest as a potential target for therapeutics designed to treat conditions associated with low bone mass, such as osteoporosis. We have determined the structure of sclerostin, which resulted in the identification of a previously unknown binding site for heparin, suggestive of a functional role in localizing sclerostin to the surface of target cells. We have also mapped the interaction site for an antibody that blocks the inhibition of Wnt signaling by sclerostin. This shows minimal overlap with the heparin binding site and highlights a key role for this region of sclerostin in protein interactions associated with the inhibition of Wnt signaling. The conserved N- and C-terminal arms of sclerostin were found to be unstructured, highly flexible, and unaffected by heparin binding, which suggests a role in stabilizing interactions with target proteins.
分泌型糖蛋白硬化蛋白最近已成为骨骼中Wnt信号通路的关键负调节因子，并作为治疗与低骨量相关疾病（如骨质疏松症）的潜在治疗靶点引起了广泛关注。我们已经确定了硬化蛋白的结构，这导致发现了一个以前未知的肝素结合位点，提示其在将硬化蛋白定位到靶细胞表面方面具有功能作用。我们还绘制了一种抗体的相互作用位点，该抗体可阻断硬化蛋白对Wnt信号的抑制作用。这表明与肝素结合位点的重叠最小，并突出了硬化蛋白这一区域在与Wnt信号抑制相关的蛋白质相互作用中的关键作用。发现硬化蛋白保守的N端和C端臂无结构、高度灵活且不受肝素结合的影响，这表明其在稳定与靶蛋白的相互作用中发挥作用。
