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

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