Targeting of bone morphogenetic protein complexes to heparin/heparan sulfate glycosaminoglycans in bioactive conformation
(2023) In FASEB Journal 37(1).- Abstract
Bone morphogenetic proteins (BMP) are powerful regulators of cellular processes such as proliferation, differentiation, and apoptosis. However, the specific molecular requirements controlling the bioavailability of BMPs in the extracellular matrix (ECM) are not yet fully understood. Our previous work showed that BMPs are targeted to the ECM as growth factor-prodomain (GF-PD) complexes (CPLXs) via specific interactions of their PDs. We showed that BMP-7 PD binding to the extracellular microfibril component fibrillin-1 renders the CPLXs from an open, bioactive V-shape into a closed, latent ring shape. Here, we show that specific PD interactions with heparin/heparan sulfate glycosaminoglycans (GAGs) allow to target and spatially... (More)
Bone morphogenetic proteins (BMP) are powerful regulators of cellular processes such as proliferation, differentiation, and apoptosis. However, the specific molecular requirements controlling the bioavailability of BMPs in the extracellular matrix (ECM) are not yet fully understood. Our previous work showed that BMPs are targeted to the ECM as growth factor-prodomain (GF-PD) complexes (CPLXs) via specific interactions of their PDs. We showed that BMP-7 PD binding to the extracellular microfibril component fibrillin-1 renders the CPLXs from an open, bioactive V-shape into a closed, latent ring shape. Here, we show that specific PD interactions with heparin/heparan sulfate glycosaminoglycans (GAGs) allow to target and spatially concentrate BMP-7 and BMP-9 CPLXs in bioactive V-shape conformation. However, targeting to GAGs may be BMP specific, since BMP-10 GF and CPLX do not interact with heparin. Bioactivity assays on solid phase in combination with interaction studies showed that the BMP-7 PD protects the BMP-7 GF from inactivation by heparin. By using transmission electron microscopy, molecular docking, and site-directed mutagenesis, we determined the BMP-7 PD-binding site for heparin. Further, fine-mapping of the fibrillin-1-binding site within the BMP-7 PD and molecular modeling showed that both binding sites are mutually exclusive in the open V- versus closed ring-shape conformation. Together, our data suggest that targeting exquisite BMP PD-binding sites by extracellular protein and GAG scaffolds integrates BMP GF bioavailability in a contextual manner in development, postnatal life, and connective tissue disease.
(Less)
- author
- organization
- publishing date
- 2023-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- bone morphogenetic protein, complex, ELISA-style bioactivity assay, growth factor, heparan sulfate, heparan sulfate proteoglycans, heparin, heparin affinity chromatography, molecular modeling, negative-staining transmission electron microscopy, prodomain, surface plasmon resonance, vascular endothelial growth factor
- in
- FASEB Journal
- volume
- 37
- issue
- 1
- article number
- e22717
- publisher
- Wiley
- external identifiers
-
- scopus:85144635682
- pmid:36563024
- ISSN
- 0892-6638
- DOI
- 10.1096/fj.202200904R
- language
- English
- LU publication?
- yes
- id
- e55a9304-3007-442a-86dc-8fc8d243e65e
- date added to LUP
- 2023-02-03 12:22:51
- date last changed
- 2024-09-19 23:28:15
@article{e55a9304-3007-442a-86dc-8fc8d243e65e,
abstract = {{<p>Bone morphogenetic proteins (BMP) are powerful regulators of cellular processes such as proliferation, differentiation, and apoptosis. However, the specific molecular requirements controlling the bioavailability of BMPs in the extracellular matrix (ECM) are not yet fully understood. Our previous work showed that BMPs are targeted to the ECM as growth factor-prodomain (GF-PD) complexes (CPLXs) via specific interactions of their PDs. We showed that BMP-7 PD binding to the extracellular microfibril component fibrillin-1 renders the CPLXs from an open, bioactive V-shape into a closed, latent ring shape. Here, we show that specific PD interactions with heparin/heparan sulfate glycosaminoglycans (GAGs) allow to target and spatially concentrate BMP-7 and BMP-9 CPLXs in bioactive V-shape conformation. However, targeting to GAGs may be BMP specific, since BMP-10 GF and CPLX do not interact with heparin. Bioactivity assays on solid phase in combination with interaction studies showed that the BMP-7 PD protects the BMP-7 GF from inactivation by heparin. By using transmission electron microscopy, molecular docking, and site-directed mutagenesis, we determined the BMP-7 PD-binding site for heparin. Further, fine-mapping of the fibrillin-1-binding site within the BMP-7 PD and molecular modeling showed that both binding sites are mutually exclusive in the open V- versus closed ring-shape conformation. Together, our data suggest that targeting exquisite BMP PD-binding sites by extracellular protein and GAG scaffolds integrates BMP GF bioavailability in a contextual manner in development, postnatal life, and connective tissue disease.</p>}},
author = {{Spanou, Chara E.S. and Wohl, Alexander P. and Doherr, Sandra and Correns, Annkatrin and Sonntag, Niklas and Lütke, Steffen and Mörgelin, Matthias and Imhof, Thomas and Gebauer, Jan M. and Baumann, Ulrich and Grobe, Kay and Koch, Manuel and Sengle, Gerhard}},
issn = {{0892-6638}},
keywords = {{bone morphogenetic protein; complex; ELISA-style bioactivity assay; growth factor; heparan sulfate; heparan sulfate proteoglycans; heparin; heparin affinity chromatography; molecular modeling; negative-staining transmission electron microscopy; prodomain; surface plasmon resonance; vascular endothelial growth factor}},
language = {{eng}},
number = {{1}},
publisher = {{Wiley}},
series = {{FASEB Journal}},
title = {{Targeting of bone morphogenetic protein complexes to heparin/heparan sulfate glycosaminoglycans in bioactive conformation}},
url = {{http://dx.doi.org/10.1096/fj.202200904R}},
doi = {{10.1096/fj.202200904R}},
volume = {{37}},
year = {{2023}},
}