Department of Early Discovery Biochemistry, Genentech Research and Early Development, 1 DNA Way, South San Francisco, CA 94080, USA.
Structure. 2011 Oct 12;19(10):1433-42. doi: 10.1016/j.str.2011.07.005. Epub 2011 Sep 22.
The Wnt pathway inhibitors DKK1 and sclerostin (SOST) are important therapeutic targets in diseases involving bone loss or damage. It has been appreciated that Wnt coreceptors LRP5/6 are also important, as human missense mutations that result in bone overgrowth (bone mineral density, or BMD, mutations) cluster to the E1 propeller domain of LRP5. Here, we report a crystal structure of LRP6 E1 bound to an antibody, revealing that the E1 domain is a peptide recognition module. Remarkably, the consensus E1 binding sequence is a close match to a conserved tripeptide motif present in all Wnt inhibitors that bind LRP5/6. We show that this motif is important for DKK1 and SOST binding to LRP6 and for inhibitory function, providing a detailed structural explanation for the effect of the BMD mutations.
Wnt 通路抑制剂 DKK1 和 Sclerostin（SOST）是涉及骨丢失或损伤的疾病的重要治疗靶点。人们已经认识到，Wnt 核心受体 LRP5/6 也很重要，因为导致骨过度生长（骨密度或 BMD 突变）的人类错义突变聚集在 LRP5 的 E1 螺旋桨结构域。在这里，我们报告了 LRP6 E1 与抗体结合的晶体结构，揭示了 E1 结构域是一个肽识别模块。值得注意的是，E1 结合序列的共识与结合 LRP5/6 的所有 Wnt 抑制剂中存在的保守三肽基序非常匹配。我们表明，该基序对于 DKK1 和 SOST 与 LRP6 的结合和抑制功能很重要，为 BMD 突变的影响提供了详细的结构解释。
