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
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 | ||||||||||||||||||||||||||||||||
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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: |
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Refereed: | Yes | ||||||||||||||||||||||||||||||||
URI: | http://kups.ub.uni-koeln.de/id/eprint/15195 |
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