Prodomain processing controls BMP-10 bioactivity and targeting to fibrillin-1 in latent conformation

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Bone morphogenetic protein 10 (BMP-10) signaling through activin receptor-like kinase 1 (ALK1) is vital for vascular homeostasis and angiogenesis.
• Dysregulation of BMP-10/ALK1 signaling is implicated in cardiovascular diseases and cancer.
• Understanding BMP-10 processing is key for developing targeted therapies.

Purpose of the Study:

• To investigate the impact of proprotein convertase (PPC) processing on BMP-10 structure, bioactivity, and extracellular matrix (ECM) interactions.
• To elucidate the molecular mechanisms underlying BMP-10 activation and its binding to fibrillin-1.

Main Methods:

• In silico molecular dynamics simulations of BMP-10 cleavage.
• Negative staining and transmission electron microscopy (TEM).
• Circular dichroism spectroscopy and binding assays.

Main Results:

• PPC processing increases BMP-10 flexibility, transitioning it from a latent wide-angle to a bioactive V-shaped complex.
• Processed BMP-10 exhibits high potency in endothelial and muscle cells and binds strongly to BMP receptors.
• The N-terminal region of BMP-10 prodomain (PD) is alpha-helical and crucial for growth factor (GF) complexation.
• Only processed BMP-10 interacts with fibrillin-1, inducing a conformational change and facilitating ECM targeting.

Conclusions:

• Proprotein convertase processing is critical for activating BMP-10 bioactivity.
• Specific folding events at the PD-GF interface, induced by processing, are essential for BMP-10 function and ECM localization.
• These findings offer insights into BMP-10 regulation for therapeutic strategies targeting vascular diseases and cancer.