The role of chordin fragments generated by partial tolloid cleavage in regulating BMP activity

Troilo, Helen; Barrett, Anne L.; Wohl, Alexander P.; Jowitt, Thomas A.; Collins, Richard F.; Bayley, Christopher P.; Zuk, Alexandra V.; Sengle, Gerhard; Baldock, Clair

doi:10.1042/bst20150071

Cited by 17 publications

(15 citation statements)

References 33 publications

(44 reference statements)

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“…Moreover we show that Tsg interacts with partially cleaved chordin to increase BMP inhibition and promote further cleavage by tolloids. These findings support the physiological relevance of partially cleaved chordin as an important BMP regulator [19]. Our results point to a monomeric Tsg interacting directly with chordin or BMP and suggest that Tsg has a type-specific regulation of BMPs enabling finely controlled regulation of BMP signalling in conjunction with other regulators.…”

Section: Introductionsupporting

confidence: 83%

Structural characterization of twisted gastrulation provides insights into opposing functions on the BMP signalling pathway

et al. 2016

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Twisted gastrulation (Tsg) and chordin are secreted glycoproteins that function together as BMP (bone morphogenetic protein) antagonists to regulate BMP growth factor signalling. Chordin binds to BMPs, preventing them from interacting with their receptors and Tsg is known to strengthen this inhibitory complex. Tsg also acts as a BMP agonist by promoting cleavage of chordin by tolloid-family proteinases. Here we explore the structural mechanism through which Tsg exerts this dual activity. We have characterized the nanoscale structure of human Tsg using in-solution biomolecular analysis and show that Tsg is a globular monomer with a flattened cross shape. Tsg has a high proportion of N-linked glycans, in relation to its molecular weight, which supports a role in solubilising BMPs. Tsg binds with high affinity to the C-terminal region of chordin and was also able to inhibit BMP-7 signalling directly but did not have an effect on BMP-4 signalling. Although both Tsg and mammalian tolloid are involved in chordin cleavage, no interaction could be detected between them using surface plasmon resonance. Together these data suggest that Tsg functions as a BMP-agonist by inducing conformational change in chordin making it more susceptible to tolloid cleavage and as a BMP-antagonist either independently or via a chordin-mediated mechanism. Following single cleavage of chordin by tolloids, Tsg continues to strengthen the inhibitory complex, supporting a role for partially cleaved chordin in BMP regulation.

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Section: Introductionsupporting

confidence: 83%

Structural characterization of twisted gastrulation provides insights into opposing functions on the BMP signalling pathway

et al. 2016

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“…In this study, COL10A1 is likely to influence deposition of the other ECM proteins in the early stage after the application of mechanical stretch. Chordin, a bone morphogenetic protein (BMP) antagonist that binds to BMPs and blocks their interaction with receptors , was also upregulated at 6 h and downregulated at 12 and 24 h of stretch. Chordin is a negative regulator of endochondral ossification in embryonic sternal chondrocytes ; also, chordin can inhibit osteoblast differentiation and mineralization by regulating BMP signaling .…”

Section: Discussionmentioning

confidence: 99%

Effects of equibiaxial mechanical stretch on extracellular matrix‐related gene expression in human calvarial osteoblasts

Zhang

et al. 2018

European J Oral Sciences

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Mechanical stretch commonly promotes craniofacial suture remodeling during interceptive orthodontics. The mechanical responses of osteoblasts in craniofacial sutures play a role in suture remodeling. Moreover, the extracellular matrix (ECM) produced by osteoblasts is crucial for the transduction of mechanical signals that promote cell differentiation. Therefore, we aimed to investigate the effect of mechanical stretch on cell viability and ECM‐related gene‐expression changes in human osteoblasts. Human calvarial osteoblasts (HCObs) were subjected to 2% deformation. Caspase activity, MTT, and cell viability assays were used to estimate osteoblast apoptosis, proliferation, and viability, respectively. Real‐time RT‐PCR (RT2‐PCR) arrays were used to assess expression of cytoskeletal‐, apoptosis‐, osteogenesis‐, and ECM‐related genes. We found that mechanical stretch significantly increased osteoblast viability and cell proliferation, and decreased the activities of caspases 3 and 7. Moreover, the expression of 18 genes related to osteoblast differentiation, apoptosis, and ECM remodeling changed by more than two‐fold in a time‐dependent manner. Therefore, mechanical stretch promotes HCOb viability and alters expression of genes that are closely related to suture remodeling under mechanical stretch.

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“…By analyzing the position of the putative Sog glycosylation sites one might gain insight to explain how glycan addition may modify Sog binding to interacting partners. It has been suggested that Chordin and Sog assume a horseshoe-like conformation that enables cooperative BMP binding (Troilo et al, 2015;Larraín et al, 2000;Shimmi et al, 2005). In this arrangement, specific N-and C-terminal regions interact with BMPs (CR1, CR3 and CR4) (Sawala et al, 2012;Troilo et al, 2015), Tsg proteins (CR1 and surrounding) (Yu et al, 2004), heparan sulfate proteoglycans (CR1 and CR4) (Jasuja et al, 2004), integrin receptors (N-terminal) (Araujo et al, 2003;Larraín et al, 2000) and collagen (CR1 and CR4) (Sawala et al, 2012) (Fig.…”

Section: Discussion N-linked Glycosylation Modulates Sog Functionmentioning

confidence: 99%

N-linked glycosylation restricts the function of short gastrulation to bind and shuttle BMPs

et al. 2018

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Disorders of N-linked glycosylation are increasingly reported in the literature. However, the targets that are responsible for the associated developmental and physiological defects are largely unknown. Bone morphogenetic proteins (BMPs) act as highly dynamic complexes to regulate several functions during development. The range and strength of BMP activity depend on interactions with glycosylated protein complexes in the extracellular milieu. Here, we investigate the role of glycosylation for the function of the conserved extracellular BMP antagonist Short gastrulation (Sog). We identify conserved N-glycosylated sites and describe the effect of mutating these residues on BMP pathway activity in Drosophila. Functional analysis reveals that loss of individual Sog glycosylation sites enhances BMP antagonism and/or increases the spatial range of Sog effects in the tissue. Mechanistically, we provide evidence that N-terminal and stem glycosylation controls extracellular Sog levels and distribution. The identification of similar residues in vertebrate Chordin proteins suggests that N-glycosylation may be an evolutionarily conserved process that adds complexity to the regulation of BMP activity.

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The role of chordin fragments generated by partial tolloid cleavage in regulating BMP activity

Cited by 17 publications

References 33 publications

Structural characterization of twisted gastrulation provides insights into opposing functions on the BMP signalling pathway

Structural characterization of twisted gastrulation provides insights into opposing functions on the BMP signalling pathway

Effects of equibiaxial mechanical stretch on extracellular matrix‐related gene expression in human calvarial osteoblasts

N-linked glycosylation restricts the function of short gastrulation to bind and shuttle BMPs

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