Universität zu Köln

Troilo, Helen ORCID: 0000-0003-0537-1786, Barrett, Anne L., Zuk, Alexandra V., Lockhart-Cairns, Michael P., Wohl, Alexander P., Bayley, Christopher P., Dajani, Rana, Tunnicliffe, Richard B., Green, Lewis, Jowitt, Thomas A., Sengle, Gerhard and Baldock, Clair ORCID: 0000-0003-3497-1959 (2016). Structural characterization of twisted gastrulation provides insights into opposing functions on the BMP signalling pathway. Matrix Biol., 55. S. 49 - 63. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 1569-1802

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Abstract

Twisted gastrulation (Tsg) and chordin are secreted glycoproteins that function together as BMP (bone morphogenetic protein) antagonists to regulate BMP growth factor signalling. Chordin binds to BMPs, preventing them from interacting with their receptors and Tsg is known to strengthen this inhibitory complex. Tsg also acts as a BMP agonist by promoting cleavage of chordin by tolloid-family proteinases. Here we explore the structural mechanism through which Tsg exerts this dual activity. We have characterized the nanoscale structure of human Tsg using in-solution biomolecular analysis and show that Tsg is a globular monomer with a flattened cross shape. Tsg has a high proportion of N-linked glycans, in relation to its molecular weight, which supports a role in solubilising BMPs. Tsg binds with high affinity to the C-terminal region of chordin and was also able to inhibit BMP-7 signalling directly but did not have an effect on BMP-4 signalling. Although both Tsg and mammalian tolloid are involved in chordin cleavage, no interaction could be detected between them using surface plasmon resonance. Together these data suggest that Tsg functions as a BMP-agonist by inducing conformational change in chordin making it more susceptible to tolloid cleavage and as a BMP-antagonist either independently or via a chordin-mediated mechanism. Following single cleavage of chordin by tolloids, Tsg continues to strengthen the inhibitory complex, supporting a role for partially cleaved chordin in BMP regulation. (C) 2016 The Authors. Published by Elsevier B.V.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Troilo, Helen UNSPECIFIED orcid.org/0000-0003-0537-1786 UNSPECIFIED Barrett, Anne L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zuk, Alexandra V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lockhart-Cairns, Michael P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wohl, Alexander P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bayley, Christopher P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dajani, Rana UNSPECIFIED UNSPECIFIED UNSPECIFIED Tunnicliffe, Richard B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Green, Lewis 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:38-265854
DOI:	10.1016/j.matbio.2016.01.019
Journal or Publication Title:	Matrix Biol.
Volume:	55
Page Range:	S. 49 - 63
Date:	2016
Publisher:	ELSEVIER SCIENCE BV
Place of Publication:	AMSTERDAM
ISSN:	1569-1802
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BONE MORPHOGENETIC PROTEIN-1; SMALL-ANGLE SCATTERING; BIOLOGICAL MACROMOLECULES; CHORDIN; BINDING; ANTAGONIST; CLEAVAGE; MECHANISMS; REQUIRES; VARIANTS Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26585