Universität zu Köln

Furlan, Ariane G., Spanou, Chara E. S., Godwin, Alan R. F., Wohl, Alexander P., Zimmermann, Laura-Marie A. ORCID: 0000-0003-2126-9191, Imhof, Thomas, Koch, Manuel ORCID: 0000-0002-2962-7814, Baldock, Clair and Sengle, Gerhard (2021). A new MMP-mediated prodomain cleavage mechanism to activate bone morphogenetic proteins from the extracellular matrix. Faseb J., 35 (3). HOBOKEN: WILEY. ISSN 1530-6860

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Abstract

Since their discovery as pluripotent cytokines extractable from bone matrix, it has been speculated how bone morphogenetic proteins (BMPs) become released and activated from the extracellular matrix (ECM). In contrast to TGF-beta s, most investigated BMPs are secreted as bioactive prodomain (PD)-growth factor (GF) complexes (CPLXs). Recently, we demonstrated that PD-dependent targeting of BMP-7 CPLXs to the extracellular fibrillin microfibril (FMF) components fibrillin-1 and -2 represents a BMP sequestration mechanism by rendering the GF latent. Understanding how BMPs become activated from ECM scaffolds such as FMF is crucial to elucidate pathomechanisms characterized by aberrant BMP activation and ECM destruction. Here, we describe a new MMP-dependent BMP-7 activation mechanism from ECM-targeted pools via specific PD degradation. Using Edman sequencing and mutagenesis, we identified a new and conserved MMP-13 cleavage site within the BMP-7 PD. A degradation screen with different BMP family PDs and representative MMP family members suggested utilization of the identified site in a general MMP-driven BMP activation mechanism. Furthermore, sandwich ELISA and solid phase cleavage studies in combination with bioactivity assays, single particle TEM, and in silico molecular docking experiments provided evidence that PD cleavage by MMP-13 leads to BMP-7 CPLX disintegration and bioactive GF release.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Furlan, Ariane G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Spanou, Chara E. S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Godwin, Alan R. F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wohl, Alexander P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zimmermann, Laura-Marie A. UNSPECIFIED orcid.org/0000-0003-2126-9191 UNSPECIFIED Imhof, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Koch, Manuel UNSPECIFIED orcid.org/0000-0002-2962-7814 UNSPECIFIED Baldock, Clair UNSPECIFIED UNSPECIFIED UNSPECIFIED Sengle, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-578513
DOI:	10.1096/fj.202001264R
Journal or Publication Title:	Faseb J.
Volume:	35
Number:	3
Date:	2021
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1530-6860
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language Biochemistry & Molecular Biology; Biology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/57851