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Internal cleavage and synergy with twisted gastrulation enhance BMP inhibition by BMPER
DOI:
10.1016/j.matbio.2018.08.006
Authors:
Michael P.
Lockhart-Cairns
(Wellcome Centre for Cell-Matrix Research, University of Manchester; Diamond Light Source)
,
Karen Tzia Wei
Lim
(Wellcome Centre for Cell-Matrix Research, University of Manchester)
,
Alexandra
Zuk
(University of Cologne)
,
Alan R. F.
Godwin
(Wellcome Centre for Cell-Matrix Research, University of Manchester)
,
Stuart A.
Cain
(Wellcome Centre for Cell-Matrix Research, University of Manchester)
,
Gerhard
Sengle
(University of Cologne)
,
Clair
Baldock
(Wellcome Centre for Cell-Matrix Research, University of Manchester)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Matrix Biology
State:
Published (Approved)
Published:
August 2018
Diamond Proposal Number(s):
1580

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.
Subject Areas:
Biology and Bio-materials
Instruments:
B21-High Throughput SAXS
Other Facilities: ESRF
Added On:
22/08/2018 10:34
Documents:
1-s2.0-S0945053X18302063-main.pdf
Discipline Tags:
Structural biology
Biophysics
Life Sciences & Biotech
Technical Tags:
Scattering
Small Angle X-ray Scattering (SAXS)