A blocking monoclonal antibody reveals dimerization of intracellular domains of ALK2 associated with genetic disorders
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Takenobu Katagiri1,2, Sho Tsukamoto3,4, Mai Kuratani3
1Division of Biomedical Sciences, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama, 350-1241, Japan. katagiri@saitama-med.ac.jp.
Abstract:
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.
Insights
A new antibody, Rm0443, blocks pathological bone signaling by targeting activin receptor-like kinase 2 (ALK2). This discovery offers potential therapeutic strategies for fibrodysplasia ossificans progressiva and related conditions.
Area of Science:
- Molecular biology
- Biochemistry
- Structural biology
Background:
- Mutations in activin receptor-like kinase 2 (ALK2) drive pathological osteogenic signaling in fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma.
- Wild-type ALK2 dimerizes upon BMP7 binding, initiating osteogenic signaling, while mutant forms trigger this pathologically with activin A.
Purpose of the Study:
- To investigate the mechanism of ALK2-mediated osteogenic signaling.
- To develop a therapeutic antibody to block aberrant ALK2 activity.
- To elucidate the structural basis of antibody-mediated ALK2 inhibition.
Main Methods:
- Crystallography was used to determine the structure of the ALK2 extracellular domain complexed with a blocking antibody fragment (Rm0443).
- In vivo studies utilized a mouse model of FOP carrying the human R206H mutation to assess the antibody's efficacy.
- Biochemical assays were employed to analyze ALK2 dimerization and signaling pathways.
Main Results:
- The monoclonal antibody Rm0443 binds ALK2 extracellular domains, inducing a back-to-back dimerization on the cell membrane.
- Structural analysis revealed Rm0443 binding to specific residues (H64, F63) on opposite faces of the ligand-binding site.
- Rm0443 demonstrated efficacy in preventing heterotopic ossification in a mouse model of FOP.
Conclusions:
- Rm0443 effectively suppresses pathological ALK2 signaling by inducing specific extracellular domain dimerization.
- The antibody provides a potential therapeutic avenue for conditions characterized by aberrant ALK2 activity, including FOP.
- Understanding the structural interactions of Rm0443 with ALK2 offers insights into targeted therapeutic development.
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