Universität zu Köln

Lockhart-Cairns, Michael P., Lim, Karen Tzia Wei, Zuk, Alexandra, Godwin, Alan R. F., Cain, Stuart A., Sengle, Gerhard and Baldock, Clair ORCID: 0000-0003-3497-1959 (2019). Internal cleavage and synergy with twisted gastrulation enhance BMP inhibition by BMPER. Matrix Biol., 77. S. 73 - 87. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 1569-1802

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Abstract

Bone morphogenetic proteins (BMPs) are essential signalling molecules involved in developmental and pathological processes and are regulated in the matrix by secreted glycoproteins. One such regulator is BMP-binding endothelial cell precursor-derived regulator (BMPER) which can both inhibit and enhance BMP signalling in a context and concentration-dependent manner. Twisted gastrulation (Tsg) can also promote or ablate BMP activity but it is unclear whether Tsg and BMPER directly interact and thereby exert a synergistic function on BMP signalling. Here, we show that human BMPER binds to Tsg through the N-terminal BMP-binding region which alone more potently inhibits BMP-4 signalling than full-length BMPER. Additionally, BMPER and Tsg cooperatively inhibit BMP-4 signalling suggesting a synergistic function to dampen BMP activity. Furthermore, full-length BMPER is targeted to the plasma membrane via binding of its C-terminal region to cell surface heparan sulphate proteoglycans but the active cleavage fragment is diffusible. Small-angle X-ray scattering and electron microscopy show that BMPER has an elongated conformation allowing the N-terminal BMP-binding and C-terminal cell-interactive regions to be spatially separated. To gain insight into the regulation of BMPER bioavailability by internal cleavage, a disease-causing BMPER point mutation, P370L, previously identified in the acid-catalysed cleavage site, was introduced. The mutated protein was secreted but the mutation prevented intracellular cleavage resulting in a lack of bioactive cleavage fragment. Furthermore, mutant BMPER was extracellularly cleaved at a downstream site presumably becoming available due to the mutation. This susceptibility to extracellular proteases and loss of bioactive N-terminal cleavage fragment may result in loss of BMPER function in disease. (C) 2018 The Authors. Published by Elsevier B.V.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lockhart-Cairns, Michael P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lim, Karen Tzia Wei UNSPECIFIED UNSPECIFIED UNSPECIFIED Zuk, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Godwin, Alan R. F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cain, Stuart A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sengle, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Baldock, Clair UNSPECIFIED orcid.org/0000-0003-3497-1959 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-151953
DOI:	10.1016/j.matbio.2018.08.006
Journal or Publication Title:	Matrix Biol.
Volume:	77
Page Range:	S. 73 - 87
Date:	2019
Publisher:	ELSEVIER SCIENCE BV
Place of Publication:	AMSTERDAM
ISSN:	1569-1802
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BIOLOGICAL MACROMOLECULES; SOLUTION SCATTERING; CROSSVEINLESS-2; CHORDIN; SUITE; ULTRACENTRIFUGATION; REGULATOR; MODULATOR; PROTEINS Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15195