Tetranectin Binds to the Kringle 1‐4 Form of Angiostatin and Modifies Its Functional Activity

Mogues, Tirsit; Etzerodt, Michael; Hall, Crystal; Engelich, Georg; Graversen, Jonas Heilskov; Hartshorn, Kevan L.

doi:10.1155/s1110724304307096

Cited by 33 publications

(25 citation statements)

References 28 publications

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“…TN is released by platelets on their activation by thrombin and probably participates in thrombus dissolution. Its biological role is probably based on its binding capacities; it binds to plasminogen kringle 4 domain and to ASTK1-4, enhancing plasminogen activation by tissue-type plasminogen activator and partially counteracting the ability of ASTK1-4 to inhibit the proliferation of endothelial cells (13). Decreased plasma TN levels were found in patients with CAD with gradually lower values from stable to unstable angina until acute myocardial infarction, and therapeutic treatment with rtPA has resulted in an increase of plasma TN levels (24,25).…”

Section: Discussionmentioning

confidence: 99%

“…Its biological role is probably based on its binding capacities; it binds to plasminogen kringle 4 domain and to kringle 1-4 domains of angiostatin (ASTK1-4). Thus, it enhances plasminogen activation by tissue-type plasminogen activator (12) and partially counteracts the ability of ASTK1-4 to inhibit the proliferation of endothelial cells (13).…”

Section: Introductionmentioning

confidence: 99%

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Alterations in biomarkers of endothelial function following on‐pump coronary artery revascularization

Panagiotopoulos¹,

Palatianos²,

Michalopoulos³

et al. 2010

Clinical Laboratory Analysis

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Alterations in biomarkers of endothelial function following on‐pump coronary artery revascularization

Panagiotopoulos¹,

Palatianos²,

Michalopoulos³

et al. 2010

Clinical Laboratory Analysis

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“…amyloid proteins) observed in this study, but numerous low-abundance species such as kallikreins, cytokines, and chemokines were also identified. Several proteins that modulate angiogenesis, including kininogen (42), tetranectin (43), secretoneurin (44), and netrin-1 (45) were identified in the CSF when the tumor was present, but were absent or poorly expressed following tumor resection. These findings demonstrate that the protein content of CSF can potentially be used as a diagnostic for the overall profile of the brain proteome, and a straightforward fractionation strategy combined with MS/MS is entirely capable of characterizing a significant fraction of the CSF proteome.…”

Section: Identification Of Biomarkers In Cerebrospinal Fluidmentioning

confidence: 99%

Biomarkers: Mining the Biofluid Proteome

Veenstra

Conrads

Hood

et al. 2005

Molecular & Cellular Proteomics

232

149

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Proteomics has brought with it the hope of identifying novel biomarkers for diseases such as cancer. This hope is built on the ability of proteomic technologies, such as mass spectrometry (MS), to identify hundreds of proteins in complex biofluids such as plasma and serum. There are many factors that make this research very challenging beginning with the lack of standardization of sample collection and continuing through the entire analytical process. Fortunately the advances made in the characterization of biofluids using proteomic techniques have been rapid and suggest that these mainly discovery driven approaches will lead to the development of highly specific platforms for diagnosing diseases and monitoring responses to different treatments in the near future.

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“…Tetranectin is a homotrimeric human protein found in both plasma and tissue. This protein binds the lysine-binding kringle domains from apolipoprotein A (2), plasminogen (3), and angiostatin (4). Tetranectin is a 60-kDa protein built from a structural unit composed of three identical chains, each with a CTLD domain located C-terminally to a trimerizing coil-coil region (5).…”

mentioning

confidence: 99%

Selection of a Novel and Highly Specific Tumor Necrosis Factor α (TNFα) Antagonist

Byla

Andersen

Holtet

et al. 2010

Journal of Biological Chemistry

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Inhibition of tumor necrosis factor ␣ (TNF␣) is a favorable way of treating several important diseases such as rheumatoid arthritis, Crohn disease, and psoriasis. Therefore, an extensive range of TNF␣ inhibitory proteins, most of them based upon an antibody scaffold, has been developed and used with variable success as therapeutics. We have developed a novel technology platform using C-type lectins as a vehicle for the creation of novel trimeric therapeutic proteins with increased avidity and unique properties as compared with current protein therapeutics. We chose human TNF␣ as a test target to validate this new technology because of the extensive experience available with protein-based TNF␣ antagonists. Here, we present a novel and highly specific TNF␣ antagonist developed using this technology. Furthermore, we have solved the three-dimensional structure of the antagonist-TNF␣ complex by x-ray crystallography, and this structure is presented here. The structure has given us a unique insight into how the selection procedure works at a molecular level. Surprisingly little change is observed in the C-type lectin-like domain structure outside of the randomized regions, whereas a substantial change is observed within the randomized loops. Thus, the overall integrity of the C-type lectin-like domain is maintained, whereas specificity and binding affinity are changed by the introduction of a number of specific contacts with TNF␣.Tetranectin belongs to the large class of C-type lectins characterized by a common fold known as the C-type lectin-like domain (CTLD) 3 (1). Tetranectin is a homotrimeric human protein found in both plasma and tissue. This protein binds the lysine-binding kringle domains from apolipoprotein A (2), plasminogen (3), and angiostatin (4). Tetranectin is a 60-kDa protein built from a structural unit composed of three identical chains, each with a CTLD domain located C-terminally to a trimerizing coil-coil region (5). The CTLD domains retain their structural integrity as separate protein domains, (6, 7) and, moreover, it was shown that their binding to the known tetranectin ligand, plasminogen kringle-4, exhibits the same thermodynamic parameters, irrespective of whether it was analyzed in the form of free monomeric domains or as tethered domains in the complete homotrimeric protein (3). In addition, the thermodynamic analysis showed that the formation of the trimer led to an apparent 100-fold affinity increase, which most likely is due to the avidity effect caused by the three-fold clustering of CTLD domains in the complete protein. Comparison of ensembles of natural CTLD domains for which the known structure and ligand specificity are known shows that the ligand-binding site can accommodate a diverse range of ligands. We therefore concluded that the tetranectin CTLD might be a useful scaffold for designing novel protein therapeutics. We could change the sequence of loops within the CTLD scaffold in the monomeric version without perturbing the overall structure. Thus, CTLD serves as an efficient s...

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Tetranectin Binds to the Kringle 1‐4 Form of Angiostatin and Modifies Its Functional Activity

Cited by 33 publications

References 28 publications

Alterations in biomarkers of endothelial function following on‐pump coronary artery revascularization

Alterations in biomarkers of endothelial function following on‐pump coronary artery revascularization

Biomarkers: Mining the Biofluid Proteome

Selection of a Novel and Highly Specific Tumor Necrosis Factor α (TNFα) Antagonist

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