Universität zu Köln

Spanou, Chara E. S. ORCID: 0000-0002-9983-7737, Yang, Chengeng ORCID: 0000-0003-3431-3753, Godwin, Alan R. F. ORCID: 0000-0002-7290-3757, Morosky, Stefanie ORCID: 0000-0003-2273-6003, Anbalagan, Arulselvi, Lütke, Steffen ORCID: 0000-0001-6924-7990, Mörgelin, Matthias ORCID: 0000-0002-6212-6990, Marcous, Fady ORCID: 0009-0006-2209-7773, Aziz, Ubair ORCID: 0000-0002-0331-1483, Wohl, Alexander P. ORCID: 0000-0003-0323-8156, Jabeen, Ishrat ORCID: 0000-0002-6660-6764, Koch, Manuel ORCID: 0000-0002-2962-7814, Jowitt, Thomas A. ORCID: 0000-0002-4045-0933, Roman, Beth L. ORCID: 0000-0002-1250-1705, Tarakanova, Anna ORCID: 0000-0002-6093-031X, Baldock, Clair ORCID: 0000-0003-3497-1959 and Sengle, Gerhard ORCID: 0000-0003-3932-1242 (2025). Prodomain processing controls BMP-10 bioactivity and targeting to fibrillin-1 in latent conformation. The FASEB Journal, 39 (3). pp. 1-27. Wiley. ISSN 0892-6638

PDF The FASEB Journal - 2025 - Spanou - Prodomain processing controls BMP‐10 bioactivity and targeting to fibrillin‐1 in latent.pdf Bereitstellung unter der CC-Lizenz: Creative Commons Attribution. Download (6MB)

Abstract

[Article Nr. e70373] 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.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Spanou, Chara E. S. UNSPECIFIED https://orcid.org/0000-0002-9983-7737 UNSPECIFIED Yang, Chengeng UNSPECIFIED https://orcid.org/0000-0003-3431-3753 UNSPECIFIED Godwin, Alan R. F. UNSPECIFIED https://orcid.org/0000-0002-7290-3757 UNSPECIFIED Morosky, Stefanie UNSPECIFIED https://orcid.org/0000-0003-2273-6003 UNSPECIFIED Anbalagan, Arulselvi UNSPECIFIED UNSPECIFIED UNSPECIFIED Lütke, Steffen UNSPECIFIED https://orcid.org/0000-0001-6924-7990 UNSPECIFIED Mörgelin, Matthias UNSPECIFIED https://orcid.org/0000-0002-6212-6990 UNSPECIFIED Marcous, Fady UNSPECIFIED https://orcid.org/0009-0006-2209-7773 UNSPECIFIED Aziz, Ubair UNSPECIFIED https://orcid.org/0000-0002-0331-1483 UNSPECIFIED Wohl, Alexander P. UNSPECIFIED https://orcid.org/0000-0003-0323-8156 UNSPECIFIED Jabeen, Ishrat UNSPECIFIED https://orcid.org/0000-0002-6660-6764 UNSPECIFIED Koch, Manuel UNSPECIFIED https://orcid.org/0000-0002-2962-7814 UNSPECIFIED Jowitt, Thomas A. UNSPECIFIED https://orcid.org/0000-0002-4045-0933 UNSPECIFIED Roman, Beth L. UNSPECIFIED https://orcid.org/0000-0002-1250-1705 UNSPECIFIED Tarakanova, Anna UNSPECIFIED https://orcid.org/0000-0002-6093-031X UNSPECIFIED Baldock, Clair UNSPECIFIED https://orcid.org/0000-0003-3497-1959 UNSPECIFIED Sengle, Gerhard UNSPECIFIED https://orcid.org/0000-0003-3932-1242 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-793960
Identification Number:	10.1096/fj.202401694R
Journal or Publication Title:	The FASEB Journal
Volume:	39
Number:	3
Page Range:	pp. 1-27
Date:	15 February 2025
Publisher:	Wiley
ISSN:	0892-6638
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Biochemie > Zentrum für Biochemie Faculty of Medicine > Sonstiges > Institut für orale muskuloskelettale Biologie Zentrum für Molekulare Medizin Faculty of Medicine > Kinder- und Jugendmedizin > Klinik und Poliklinik für Kinder- und Jugendmedizin
Subjects:	Life sciences Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/79396