Mammalian BMP-1/Tolloid-Related Metalloproteinases, Including Novel Family Member Mammalian Tolloid-Like 2, Have Differential Enzymatic Activities and Distributions of Expression Relevant to Patterning and Skeletogenesis

Scott, Ian C.; Blitz, Ira L.; Pappano, William N.; Imamura, Yasutada; Clark, Timothy G.; Steiglitz, Barry M.; Thomas, Christina L.; Maas, Sarah A.; Takahara, Kazuhiko; Cho, Ken W.Y.; Greenspan, Daniel S.

doi:10.1006/dbio.1999.9383

Cited by 252 publications

(193 citation statements)

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“…Similarly, the vertebrate SOG orthologue Chordin is cleaved in vitro, at two sites (Fig. 5A), and counteracted in overexpression assays in Xenopus and zebrafish embryos, by various BMP1/TLD-like proteinases (Blader et al, 1997;Dale et al, 2002;Piccolo et al, 1996;Scott et al, 1999;Wardle et al, 1999). In mammals, BMP1 and mTLL1, but not mTLD or mTLL2, are capable of cleaving Chordin in vitro ; and products of the Bmp1 and Tll1 genes are responsible for cleaving Chordin in vivo .…”

Section: Bmps 2 Andmentioning

confidence: 98%

“…Subsequent to the finding that BMP1 provides pCP activity (Kessler et al, 1996;Li et al, 1996), it was shown that each of the mammalian BMP1/TLD-like proteinases has some level of pCP activity; with BMP1 and mTLL2 showing highest and lowest in vitro pCP levels, respectively Scott et al, 1999). In fact, mTLL2 pCP levels are not observable in vitro, unless procollagen substrates and mTLL2 are co-incubated in the presence of a third protein known to enhance the pCP activity of BMP1/TLD-like proteinases and see below).…”

Section: Fibrillar Collagensmentioning

confidence: 99%

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The bone morphogenetic protein 1/Tolloid-like metalloproteinases

2007

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A decade ago, bone morphogenetic protein 1 (BMP1) was shown to provide the activity necessary for proteolytic removal of the C-propeptides of procollagens I-III: precursors of the major fibrillar collagens. Subsequent studies have shown BMP1 to be the prototype of a small group of extracellular metalloproteinases that play manifold roles in regulating formation of the extracellular matrix (ECM). Soon after initial cloning of BMP1, genetic studies showed the related Drosophila proteinase Tolloid (TLD) to be necessary for formation of the dorsal-ventral axis in early embryogenesis. It is now clear that the BMP1/TLD-like proteinases, conserved in species ranging from Drosophila to humans, act in dorsal-ventral patterning via activation of transforming growth factor β (TGFβ)-like proteins BMP2, BMP4 (vertebrates) and decapentaplegic (arthropods). More recently, it has become apparent that the BMP1/TLD-like proteinases are key activators of a broader subset of the TGFβ superfamily of proteins, with implications that these proteinases may be key in orchestrating formation of ECM with growth factor activation and BMP signaling in morphogenetic processes.

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Section: Bmps 2 Andmentioning

confidence: 98%

Section: Fibrillar Collagensmentioning

confidence: 99%

The bone morphogenetic protein 1/Tolloid-like metalloproteinases

2007

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“…Subsequent work showed that BMP-1 is a smaller spliced variant of mTld (4). The functions of BMP-1 remained unknown until it was shown that it can cleave chordin, an antagonist of BMP-2, which can direct bone and cartilage formation (5).…”

Section: Bmp-1mentioning

confidence: 99%

Bone Morphogenetic Protein-1 (BMP-1)

Hartigan

Garrigue‐Antar

Kadler

2003

Journal of Biological Chemistry

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Bone morphogenetic protein-1 (BMP-1) is a shorter spliced variant of mammalian tolloid (mTld), both of which cleave the C-propeptides of type I procollagen during the synthesis of extracellular matrix collagen fibrils. The fact that BMP-1 and mTld both exhibit procollagen C-proteinase (PCP) activity and that BMP-1 is the smaller variant might indicate that BMP-1 comprises the minimal required sequences for PCP activity. BMP-1 comprises a metalloproteinase domain, three CUB domains, and an epidermal growth factor (EGF)-like domain, which is located between the second and third CUB (complement components C1r/C1s, the sea urchin protein Uegf, and BMP-1) domains. In this study we showed the following. 1) The CUB1 domain is required for secretion of the molecule. Domain swapping experiments, in which CUB1 and other CUB domains were interchanged, resulted in retention of the proteins by cells. Therefore, CUB1 and its location immediately adjacent to the metalloproteinase domain are essential for secretion of the protein. 2) Mutants lacking the EGFlike and CUB3 domains exhibited full C-proteinase activity. In contrast, mutants lacking the CUB2 domain were poor C-proteinases. 3) Further studies showed that Glu-483 on the ␤4-␤5 loop of CUB2 is essential for Cproteinase activity of BMP-1. In conclusion, the study showed that the minimal domain structure for PCP activity is considerably shorter than expected and comprises the metalloproteinase domain and the CUB1 and CUB2 domains of BMP-1. BMP-11 was isolated in the latter half of the 1980s from osteogenic fragments of bone and was shown to induce cartilage formation in vivo (1, 2). Unlike other BMPs, BMP-1 is a metalloproteinase with a proteinase domain that is homologous to the crayfish enzyme astacin (3) and a C-terminal domain comprising three CUB domains and one EGF-like domain. Subsequent work showed that BMP-1 is a smaller spliced variant of mTld (4). The functions of BMP-1 remained unknown until it was shown that it can cleave chordin, an antagonist of BMP-2, which can direct bone and cartilage formation (5).BMP-1 and mTld exhibit similar substrate specificity in vitro in that they can cleave precursors of extracellular matrix proteins including fibrillar procollagens (6, 7), biglycan (8), type VII procollagen (9), prolysyl oxidase (10, 11), and chains of laminin (12, 13). Evidence from gene knock-out studies in mice in which the mouse tolloid gene was mutated showed that BMP-1 and/or mTld are essential for normal assembly of extracellular matrix (14). Electron microscopy of the skin detected the presence of abnormal collagen fibrils in the knock-out mouse, which showed that BMP-1 and/or mTld are essential for normal cleavage of procollagen.BMP-1 is encoded by mtld, which also gives rise to mammalian tolloid (mTld or vertebrate Tld). mTld contains five CUB domains and two EGF-like domains at its C terminus, whereas BMP-1 lacks the most C-terminal two CUBs and one EGF-like domain. Interestingly, both BMP-1 and mTld can cleave the C-propeptides of fibril-forming proc...

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“…Members of the BMP-1/tolloid family of metalloproteinases cleave chordin at two sites, immediately downstream of vWC1 and -3 (12,13). Tsg can also promote cleavage of chordin by tolloids and has a role in increasing the turnover of chordin fragments (14).…”

mentioning

confidence: 99%

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 BMP-1/Tolloid-Related Metalloproteinases, Including Novel Family Member Mammalian Tolloid-Like 2, Have Differential Enzymatic Activities and Distributions of Expression Relevant to Patterning and Skeletogenesis

Cited by 252 publications

References 41 publications

The bone morphogenetic protein 1/Tolloid-like metalloproteinases

The bone morphogenetic protein 1/Tolloid-like metalloproteinases

Bone Morphogenetic Protein-1 (BMP-1)

Nanoscale structure of the BMP antagonist chordin supports cooperative BMP binding

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