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

Spanou, Chara E.S. ; Yang, Chengeng ; Godwin, Alan R.F. ; Morosky, Stefanie ; Anbalagan, Arulselvi ; Lütke, Steffen ; Mörgelin, Matthias LU ; Marcous, Fady ; Aziz, Ubair and Wohl, Alexander P. , et al. (2025) In FASEB Journal 39(3).
Abstract

Bone morphogenetic protein 10 (BMP-10) is crucial for endothelial cell signaling via activin receptor-like kinase 1 (ALK1), a pathway central to vascular homeostasis and angiogenesis. Dysregulated BMP-10 signaling contributes to cardiovascular diseases and cancer, highlighting the need to control ALK1-mediated endothelial responses to BMP-10 for therapeutic development. BMP-10 biosynthesis involves processing by proprotein convertases (PPCs) resulting in a non-covalently associated prodomain–growth factor (PD–GF) complex (CPLX), similar to other TGF-β superfamily ligands. However, the molecular requirements for BMP-10 bioactivity remain unclear. We investigated how PPC processing impacts BMP-10 structure, bioactivity, and its... (More)

Bone morphogenetic protein 10 (BMP-10) is crucial for endothelial cell signaling via activin receptor-like kinase 1 (ALK1), a pathway central to vascular homeostasis and angiogenesis. Dysregulated BMP-10 signaling contributes to cardiovascular diseases and cancer, highlighting the need to control ALK1-mediated endothelial responses to BMP-10 for therapeutic development. BMP-10 biosynthesis involves processing by proprotein convertases (PPCs) resulting in a non-covalently associated prodomain–growth factor (PD–GF) complex (CPLX), similar to other TGF-β superfamily ligands. However, the molecular requirements for BMP-10 bioactivity remain unclear. We investigated how PPC processing impacts BMP-10 structure, bioactivity, and its interaction with the extracellular matrix (ECM) protein fibrillin-1. Molecular dynamics simulations post-in silico cleavage of the BMP-10 dimer model as well as negative staining and transmission electron microscopy (TEM) revealed that PD processing increases BMP-10 flexibility converting it from a latent wide-angle conformation to a bioactive CPLX which can adopt a V-shape with tighter angle. Only processed BMP-10 demonstrated high potency in HUVEC and C2C12 cells and robust binding to immobilized BMP receptors. Circular dichroism and interaction studies revealed that the N-terminal region of the BMP-10 PD is rich in alpha-helical content, which is essential for efficient complexation with the BMP-10 GF. Binding studies and TEM analyses showed that only the processed BMP-10 CPLX interacts with the N-terminal region of fibrillin-1, causing a conformational change that renders it into a closed ring-shaped conformation. These findings suggest that PD processing induces specific folding events at the PD–GF interface, which is critical for BMP-10 bioactivity and its targeting to the ECM.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
bone morphogenetic protein, complex, conformational change, electron microscopy, furin, growth factor, molecular dynamics, molecular modeling, proprotein convertases (PPCs), single particle analysis
in
FASEB Journal
volume
39
issue
3
article number
e70373
publisher
Wiley
external identifiers
  • pmid:39921464
  • scopus:85217412945
ISSN
0892-6638
DOI
10.1096/fj.202401694R
language
English
LU publication?
yes
id
04bf4b0b-4c89-41d9-8190-506d4dd8ec24
date added to LUP
2025-03-17 15:12:42
date last changed
2025-07-08 01:18:44
@article{04bf4b0b-4c89-41d9-8190-506d4dd8ec24,
  abstract     = {{<p>Bone morphogenetic protein 10 (BMP-10) is crucial for endothelial cell signaling via activin receptor-like kinase 1 (ALK1), a pathway central to vascular homeostasis and angiogenesis. Dysregulated BMP-10 signaling contributes to cardiovascular diseases and cancer, highlighting the need to control ALK1-mediated endothelial responses to BMP-10 for therapeutic development. BMP-10 biosynthesis involves processing by proprotein convertases (PPCs) resulting in a non-covalently associated prodomain–growth factor (PD–GF) complex (CPLX), similar to other TGF-β superfamily ligands. However, the molecular requirements for BMP-10 bioactivity remain unclear. We investigated how PPC processing impacts BMP-10 structure, bioactivity, and its interaction with the extracellular matrix (ECM) protein fibrillin-1. Molecular dynamics simulations post-in silico cleavage of the BMP-10 dimer model as well as negative staining and transmission electron microscopy (TEM) revealed that PD processing increases BMP-10 flexibility converting it from a latent wide-angle conformation to a bioactive CPLX which can adopt a V-shape with tighter angle. Only processed BMP-10 demonstrated high potency in HUVEC and C2C12 cells and robust binding to immobilized BMP receptors. Circular dichroism and interaction studies revealed that the N-terminal region of the BMP-10 PD is rich in alpha-helical content, which is essential for efficient complexation with the BMP-10 GF. Binding studies and TEM analyses showed that only the processed BMP-10 CPLX interacts with the N-terminal region of fibrillin-1, causing a conformational change that renders it into a closed ring-shaped conformation. These findings suggest that PD processing induces specific folding events at the PD–GF interface, which is critical for BMP-10 bioactivity and its targeting to the ECM.</p>}},
  author       = {{Spanou, Chara E.S. and Yang, Chengeng and Godwin, Alan R.F. and Morosky, Stefanie and Anbalagan, Arulselvi and Lütke, Steffen and Mörgelin, Matthias and Marcous, Fady and Aziz, Ubair and Wohl, Alexander P. and Jabeen, Ishrat and Koch, Manuel and Jowitt, Thomas A. and Roman, Beth L. and Tarakanova, Anna and Baldock, Clair and Sengle, Gerhard}},
  issn         = {{0892-6638}},
  keywords     = {{bone morphogenetic protein; complex; conformational change; electron microscopy; furin; growth factor; molecular dynamics; molecular modeling; proprotein convertases (PPCs); single particle analysis}},
  language     = {{eng}},
  number       = {{3}},
  publisher    = {{Wiley}},
  series       = {{FASEB Journal}},
  title        = {{Prodomain processing controls BMP-10 bioactivity and targeting to fibrillin-1 in latent conformation}},
  url          = {{http://dx.doi.org/10.1096/fj.202401694R}},
  doi          = {{10.1096/fj.202401694R}},
  volume       = {{39}},
  year         = {{2025}},
}