Universität zu Köln

Troilo, Helen ORCID: 0000-0003-0537-1786, Zuk, Alexandra V., Tunnicliffe, Richard B., Wohl, Alexander P., Berry, Richard, Collins, Richard F., Jowitt, Thomas A., Sengle, Gerhard and Baldock, Clair ORCID: 0000-0003-3497-1959 (2014). Nanoscale structure of the BMP antagonist chordin supports cooperative BMP binding. Proc. Natl. Acad. Sci. U. S. A., 111 (36). S. 13063 - 13069. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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Abstract

Bone morphogenetic proteins (BMPs) orchestrate key cellular events, such as proliferation and differentiation, in development and homeostasis. Extracellular antagonists, such as chordin, are essential regulators of BMP signaling. Chordin binds to BMPs blocking interaction with receptors, and cleavage by tolloid proteinases is thought to relieve this inhibition. A model has been previously proposed where chordin adopts a horseshoe-like arrangement enabling BMP binding cooperatively by terminal domains (1). Here, we present the nanoscale structure of human chordin using electron microscopy, small angle X-ray scattering, and solution-based biophysical techniques, which together show that chordin indeed has a compact horseshoe-shaped structure. Chordin variants were used to map domain locations within the chordin molecule. The terminal BMP-binding domains protrude as prongs from the main body of the chordin structure, where they are well positioned to interact with the growth factor. The spacing provided by the chordin domains supports the principle of a cooperative BMP-binding arrangement that the original model implied in which growth factors bind to both an N-and C-terminal von Willebrand factor C domain of chordin. Using binding and bioactivity assays, we compared full-length chordin with two truncated chordin variants, such as those produced by partial tolloid cleavage. Cleavage of either terminal domain has little effect on the affinity of chordin for BMP-4 and BMP-7 but C-terminal cleavage increases the efficacy of chordin as a BMP-4 inhibitor. Together these data suggest that partial tolloid cleavage is insufficient to ablate BMP inhibition and the C-terminal chordin domains play an important role in BMP regulation.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Troilo, Helen UNSPECIFIED orcid.org/0000-0003-0537-1786 UNSPECIFIED Zuk, Alexandra V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tunnicliffe, Richard B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wohl, Alexander P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Berry, Richard UNSPECIFIED UNSPECIFIED UNSPECIFIED Collins, Richard F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jowitt, Thomas A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sengle, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Baldock, Clair UNSPECIFIED orcid.org/0000-0003-3497-1959 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-428883
DOI:	10.1073/pnas.1404166111
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	111
Number:	36
Page Range:	S. 13063 - 13069
Date:	2014
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BONE MORPHOGENETIC PROTEIN; TWISTED GASTRULATION; EXTRACELLULAR-SPACE; ELECTRON-MICROSCOPY; SPEMANN ORGANIZER; XENOPUS; DROSOPHILA; FAMILY; INHIBITION; MECHANISMS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42888