A large bioactive BMP ligand with distinct signaling properties is produced by alternative proconvertase processing

Area of Science:

• Molecular Biology
• Developmental Biology
• Biochemistry

Background:

• Transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) ligands are typically dimers of 100–140 amino acid peptides.
• These peptides are generated by proteolytic processing of proprotein precursors, often by furin.
• The functional implications of alternative processing pathways for BMP ligands remain incompletely understood.

Purpose of the Study:

• To identify and characterize novel processing products of BMP proproteins.
• To investigate the functional differences between distinct BMP ligand forms.
• To explore the role of differential BMP processing in development and disease.

Main Methods:

• Bioinformatic analysis to identify conserved furin cleavage sites in BMP proproteins.
• Expression and functional characterization of different Gbb ligand forms in Drosophila.
• Analysis of human population data linking mutations in BMP pathway genes to developmental disorders.

Main Results:

• Identification of a conserved N-terminal (NS) furin cleavage site in the Drosophila Gbb proprotein.
• Discovery of a large, 328-amino acid Gbb ligand (Gbb38) distinct from the conventional 130-amino acid form (Gbb15).
• Gbb38 demonstrated enhanced signaling activity and longer-range signaling compared to Gbb15, with tissue-specific variations in their abundance.

Conclusions:

• Differential proprotein processing can generate functionally distinct BMP ligands.
• The large Gbb38 ligand form has distinct signaling properties compared to the smaller Gbb15 form.
• NS processing of BMPs is crucial for normal development, as evidenced by human disease-associated mutations.