Universität zu Köln

Wohl, Alexander P., Troilo, Helen ORCID: 0000-0003-0537-1786, Collins, Richard F., Baldock, Clair ORCID: 0000-0003-3497-1959 and Sengle, Gerhard (2016). Extracellular Regulation of Bone Morphogenetic Protein Activity by the Microfibril Component Fibrillin-1. J. Biol. Chem., 291 (24). S. 12732 - 12747. BETHESDA: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. ISSN 1083-351X

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Abstract

Since the discovery of bone morphogenetic proteins (BMPs) as pluripotent cytokines extractable from bone matrix, it has been speculated how targeting of BMPs to the extracellular matrix (ECM) modulates their bioavailability. Understanding these processes is crucial for elucidating pathomechanisms of connective tissue disorders characterized by ECM deficiency and growth factor dysregulation. Here, we provide evidence for a new BMP targeting and sequestration mechanism that is controlled by the ECM molecule fibrillin-1. We present the nanoscale structure of the BMP-7 prodomain-growth factor complex using electron microscopy, small angle x-ray scattering, and circular dichroism spectroscopy, showing that it assumes an open V-like structure when it is bioactive. However, upon binding to fibrillin-1, the BMP-7 complex is rendered into a closed ring shape, which also confers latency to the growth factor, as demonstrated by bioactivity measurements. BMP-7 prodomain variants were used to map the critical epitopes for prodomain-growth factor and prodomain-prodomain binding. Together, these data show that upon prodomain binding to fibrillin-1, the BMP-7 complex undergoes a conformational change, which denies access of BMP receptors to the growth factor.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wohl, Alexander P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Troilo, Helen UNSPECIFIED orcid.org/0000-0003-0537-1786 UNSPECIFIED Collins, Richard F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Baldock, Clair UNSPECIFIED orcid.org/0000-0003-3497-1959 UNSPECIFIED Sengle, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-272372
DOI:	10.1074/jbc.M115.704734
Journal or Publication Title:	J. Biol. Chem.
Volume:	291
Number:	24
Page Range:	S. 12732 - 12747
Date:	2016
Publisher:	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Place of Publication:	BETHESDA
ISSN:	1083-351X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CIRCULAR-DICHROISM SPECTROSCOPY; TGF-BETA; SECONDARY STRUCTURE; MARFAN-SYNDROME; GROWTH; ACTIVATION; PRODOMAIN; RECEPTORS; SPECTRA; COMPETE Multiple languages Biochemistry & Molecular Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27237