A blocking monoclonal antibody reveals dimerization of intracellular domains of ALK2 associated with genetic disorders

Mutant forms of the transmembrane receptor activin receptor-like kinase 2 are associated with different genetic diseases. Here, the authors report that disease-associated forms of this receptor cause intracellular domains to dimerize in response to ligand binding of extracellular domains. 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.

Automated summary

Mutations in the transmembrane receptor activin receptor-like kinase 2 (ALK2) cause abnormal signaling in various genetic diseases. The authors found that disease-associated ALK2 forms can dimerize intracellularly upon ligand binding. They developed a blocking antibody that inhibits ALK2 signaling and demonstrated its potential in suppressing pathological bone formation in a mouse model of fibrodysplasia ossificans progressiva.