Internal cleavage and synergy with twisted gastrulation enhance BMP inhibition by BMPER.
Animals
Binding Sites
Bone Morphogenetic Protein 4
/ chemistry
Carrier Proteins
/ chemistry
Cell Line, Transformed
Cloning, Molecular
Gene Expression Regulation
Genetic Vectors
/ chemistry
HEK293 Cells
Humans
Kinetics
Mice
Models, Molecular
Myoblasts
/ cytology
Protein Binding
Protein Interaction Domains and Motifs
Protein Structure, Secondary
Proteins
/ chemistry
Proteolysis
Recombinant Proteins
/ chemistry
Signal Transduction
Journal
Matrix biology : journal of the International Society for Matrix Biology
ISSN: 1569-1802
Titre abrégé: Matrix Biol
Pays: Netherlands
ID NLM: 9432592
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
23
05
2018
revised:
13
08
2018
accepted:
16
08
2018
pubmed:
21
8
2018
medline:
3
8
2019
entrez:
21
8
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30125619
pii: S0945-053X(18)30206-3
doi: 10.1016/j.matbio.2018.08.006
pmc: PMC6456722
pii:
doi:
Substances chimiques
BMP4 protein, human
0
BMPER protein, human
0
Bone Morphogenetic Protein 4
0
Carrier Proteins
0
Proteins
0
Recombinant Proteins
0
TWSG1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
73-86Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/R008221/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/L00612X/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 088785/Z/09/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L011840/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/N015398/1
Pays : United Kingdom
Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
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