von Willebrand Factor Type C Domain-containing Proteins Regulate Bone Morphogenetic Protein Signaling through Different Recognition Mechanisms

Zhang, Jinli; Huang, Yi; Qiu, Liyan; Nickel, J. Curtis; Sebald, Walter

doi:10.1074/jbc.m700456200

Cited by 104 publications

(160 citation statements)

References 56 publications

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“…The Dpp/Scw heterodimer and Tsg together, but neither of them alone, can release Sog from VkgC (11), suggesting that each-Dpp/Scw and Tsgcompetes with one of the two collagen IV binding sites on Sog. In vertebrates, the Dpp ortholog BMP2 and Tsg both bind strongly to CR1 and CR3 (15,16), whereas the Scw-related protein BMP7 interacts preferentially with CR1 and CR4 (15) (Fig. 4A).…”

Section: Resultsmentioning

confidence: 99%

Multistep molecular mechanism for Bone morphogenetic protein extracellular transport in the Drosophila embryo

Sawala

Sutcliffe

Ashe

2012

Proc. Natl. Acad. Sci. U.S.A.

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In the Drosophila embryo, formation of a bone morphogenetic protein (BMP) morphogen gradient requires transport of a heterodimer of the BMPs Decapentaplegic (Dpp) and Screw (Scw) in a protein shuttling complex. Although the core components of the shuttling complex-Short Gastrulation (Sog) and Twisted Gastrulation (Tsg)-have been identified, key aspects of this shuttling system remain mechanistically unresolved. Recently, we discovered that the extracellular matrix protein collagen IV is important for BMP gradient formation. Here, we formulate a molecular mechanism of BMP shuttling that is catalyzed by collagen IV. We show that Dpp is the only BMP ligand in Drosophila that binds collagen IV. A collagen IV binding-deficient Dpp mutant signals at longer range in vivo, indicating that collagen IV functions to immobilize free Dpp in the embryo. We also provide in vivo evidence that collagen IV functions as a scaffold to promote shuttling complex assembly in a multistep process. After binding of Dpp/ Scw and Sog to collagen IV, protein interactions are remodeled, generating an intermediate complex in which Dpp/Scw-Sog is poised for release by Tsg through specific disruption of a collagen IV-Sog interaction. Because all components are evolutionarily conserved, we propose that regulation of BMP shuttling and immobilization through extracellular matrix interactions is widely used, both during development and in tissue homeostasis, to achieve a precise extracellular BMP distribution.

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Section: Resultsmentioning

confidence: 99%

Multistep molecular mechanism for Bone morphogenetic protein extracellular transport in the Drosophila embryo

Sawala

Sutcliffe

Ashe

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…To understand how chordin may interact with BMP, we assumed a 1:1 interaction of one chordin monomer to one BMP dimer based on BMP-2 binding data by Zhang et al (9) and for BMP-4 and -7 shown in Table 1. These data show that the avidity of chordin for BMP does not decrease with the growth factor immobilized, suggesting that two BMP binding domains of chordin can interact with one BMP dimer.…”

Section: Resultsmentioning

confidence: 99%

“…The BMP binding and biological activities of chordin reside in the vWC domains, particularly vWC1 and -3 (1). Previous binding analysis suggests that, whereas vWC1 can bind to different BMPs with high affinity, vWC3 specifically binds to BMP-2 and BMP-4 (1), and vWC4 to BMP-7 (9). The individual vWC domains have decreased biological activity compared with full-length chordin (1), which suggests that chordin may bind BMP cooperatively via a vWC domain from each terminus.…”

mentioning

confidence: 99%

“…1B). It is thought that the interaction with BMP occurs in a ratio of one chordin molecule to one BMP dimer (5,9,10). The CHRD domains, which are also found in a number of microbial proteins (11), are not thought to bind BMP but may alter the avidity of chordin for BMP by facilitating cooperative binding.…”

mentioning

confidence: 99%

“…Tsg can also promote cleavage of chordin by tolloids and has a role in increasing the turnover of chordin fragments (14). Following tolloid cleavage, chordin is unable to antagonize BMP activity (13) but the vWC-domain-containing chordin fragments retain the ability to bind BMP (9). In some circumstances, truncation of the Drosophila homolog, Sog, can lead to gain of function (15).…”

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confidence: 99%

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Nanoscale structure of the BMP antagonist chordin supports cooperative BMP binding

Troilo

Zuk²,

Tunnicliffe

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Bone morphogenetic proteins (BMPs) orchestrate key cellular events, such as proliferation and differentiation, in development and homeostasis. Extracellular antagonists, such as chordin, are essential regulators of BMP signaling. Chordin binds to BMPs blocking interaction with receptors, and cleavage by tolloid proteinases is thought to relieve this inhibition. A model has been previously proposed where chordin adopts a horseshoe-like arrangement enabling BMP binding cooperatively by terminal domains (1). Here, we present the nanoscale structure of human chordin using electron microscopy, small angle X-ray scattering, and solution-based biophysical techniques, which together show that chordin indeed has a compact horseshoe-shaped structure. Chordin variants were used to map domain locations within the chordin molecule. The terminal BMP-binding domains protrude as prongs from the main body of the chordin structure, where they are well positioned to interact with the growth factor. The spacing provided by the chordin domains supports the principle of a cooperative BMP-binding arrangement that the original model implied in which growth factors bind to both an N-and C-terminal von Willebrand factor C domain of chordin. Using binding and bioactivity assays, we compared full-length chordin with two truncated chordin variants, such as those produced by partial tolloid cleavage. Cleavage of either terminal domain has little effect on the affinity of chordin for BMP-4 and BMP-7 but C-terminal cleavage increases the efficacy of chordin as a BMP-4 inhibitor. Together these data suggest that partial tolloid cleavage is insufficient to ablate BMP inhibition and the C-terminal chordin domains play an important role in BMP regulation.

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Mammalian tolloid proteinases: role in growth factor signalling

et al. 2016

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Tolloid proteinases are essential for tissue patterning and extracellular matrix assembly. The members of the family differ in their substrate specificity and activity, despite sharing similar domain organization. The mechanisms underlying substrate specificity and activity are complex, with variation between family members, and depend on both multimerization and substrate interaction. In addition, enhancers, such as Twisted gastrulation (Tsg), promote cleavage of tolloid substrate, chordin, to regulate growth factor signalling. Although Tsg and mammalian tolloid (mTLD) are involved in chordin cleavage, no interaction has been detected between them, suggesting Tsg induces a change in chordin to increase susceptibility to cleavage. All members of the tolloid family bind the N terminus of latent TGFβ‐binding protein‐1, providing support for their role in TGFβ signalling.

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von Willebrand Factor Type C Domain-containing Proteins Regulate Bone Morphogenetic Protein Signaling through Different Recognition Mechanisms

Cited by 104 publications

References 56 publications

Multistep molecular mechanism for Bone morphogenetic protein extracellular transport in the Drosophila embryo

Multistep molecular mechanism for Bone morphogenetic protein extracellular transport in the Drosophila embryo

Nanoscale structure of the BMP antagonist chordin supports cooperative BMP binding

Mammalian tolloid proteinases: role in growth factor signalling

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