Mutations in activin receptor-like kinase 2 (ALK2) can cause the pathological osteogenic signaling seen in some patients with fibrodysplasia ossificans progressiva and other conditions such as diffuse intrinsic pontine glioma. Here, we report that intracellular domain of wild-type ALK2 readily dimerizes in response to BMP7 binding to drive osteogenic signaling. This osteogenic signaling is pathologically triggered by heterotetramers of type II receptor kinases and ALK2 mutant forms, which form intracellular domain dimers in response to activin A binding. We develop a blocking monoclonal antibody, Rm0443, that can suppress ALK2 signaling. We solve the crystal structure of the ALK2 extracellular domain complex with a Fab fragment of Rm0443 and show that Rm0443 induces dimerization of ALK2 extracellular domains in a back-to-back orientation on the cell membrane by binding the residues H64 and F63 on opposite faces of the ligand-binding site. Rm0443 could prevent heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva that carries the human R206H pathogenic mutant.

激活素受体样激酶 2 (ALK2) 的突变可导致一些患有进行性骨化性纤维发育不良和其他疾病（例如弥漫性内源性脑桥神经胶质瘤）的患者出现病理性成骨信号传导。在这里，我们报告野生型 ALK2 的胞内结构域很容易响应 BMP7 结合而二聚化，以驱动成骨信号传导。这种成骨信号传导是由 II 型受体激酶和 ALK2 突变形式的异四聚体病理触发的，这些异四聚体响应激活素 A 结合而形成细胞内结构域二聚体。我们开发了一种阻断性单克隆抗体 Rm0443，它可以抑制 ALK2 信号传导。我们用 Rm0443 的 Fab 片段解析了 ALK2 胞外结构域复合物的晶体结构，并表明 Rm0443 通过结合残基 H64 和 F63 在细胞膜上以背靠背方向诱导 ALK2 胞外结构域二聚化。配体结合位点。Rm0443 可以预防携带人类 R206H 致病突变体的进行性骨化性纤维发育不良小鼠模型中的异位骨化。