Division of Biomedical Sciences, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama, 350-1241, Japan.
Project of Clinical and Basic Research for FOP, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama, 350-1241, Japan.
Nat Commun. 2023 May 25;14(1):2960. doi: 10.1038/s41467-023-38746-5.
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.
ALK2 激酶（activin receptor-like kinase 2）突变可导致进行性骨化性纤维发育不良（fibrodysplasia ossificans progressiva）和弥漫性内生脑桥胶质瘤等一些病症中出现病理性成骨信号。在此，我们报告野生型 ALK2 的细胞内结构域可通过 BMP7 与 ALK2 的结合而迅速二聚化，进而驱动成骨信号。该成骨信号由 II 型受体激酶和 ALK2 突变形式的杂四聚体异常触发，后者通过结合激活素 A 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。我们解析了 Rm0443 的 Fab 片段与 ALK2 细胞外结构域复合物的晶体结构，并表明 Rm0443 通过结合配体结合位点相对面上的残基 H64 和 F63，在细胞膜上以背对背的方式诱导 ALK2 细胞外结构域的二聚化。Rm0443 可预防携带人类 R206H 致病性突变的进行性骨化性纤维发育不良小鼠模型中的异位骨化。
