Specificities of Heparin-binding Sites from the Amino-Terminus and Type 1 Repeats of Thrombospondin-1

Yu, Haixia; Tyrrell, D J; Cashel, JoAnne; Guo, Neng-hua; Vogel, Thomas; Sipes, John M.; Lam, Lun; Fillit, Howard; Hartman, Jacob R.; Mendelovitz, Simona; Panel, Amos; Roberts, David D.

doi:10.1006/abbi.1999.1597

Cited by 28 publications

(22 citation statements)

References 61 publications

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“…Instead, we observed a significant enhancement of TSP1 binding to heparin in the presence of 4B6 and 2D11 relative to TSP1 alone or TSP1 complexed with a control TSP1 antibody ahTSP (HB8432), which binds to an epitope in the EGF-like repeats (Annis et al, 2006;Annis et al, 2007). Consistent with the finding that the heparin binding site overlaps with a sulfatidebinding site in the N-module (Yu et al, 2000), antibodies 4B6 and 2D11 and, to a lesser extent, 5H9 enhanced TSP1 binding to sulfatide (Fig. 5B).…”

Section: Effects Of Mabs On Sulfated Glycoconjugate Binding To the N supporting

confidence: 83%

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Calcium indirectly regulates immunochemical reactivity and functional activities of the N-domain of thrombospondin-1

et al. 2008

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Conformational changes induced in thrombospondin-1 by removal of calcium regulate interactions with some ligands of its N-modules. Because calcium binds primarily to elements of the C-terminal signature domain of thrombospondin-1, which are distant from the N-modules, such regulation was unexpected. To clarify the mechanism for this regulation, we compared ligand binding to the Nmodules of thrombospondin-1 in the full-length protein and recombinant trimeric thrombospondin-1 truncated prior to the signature domain. Three monoclonal antibodies were identified that recognize the N-modules, two of which exhibit calcium-dependent binding to native thrombospondin-1 but not to the truncated trimeric protein. These antibodies or calcium selectively modulate interactions of fibronectin, heparin, sulfatide, α3β1 integrin, tumor necrosis factor-α-stimulated gene-6 protein, and, to a lesser extent, α4β1 integrin with native thrombospondin-1 but not with the truncated protein.These results indicate connectivity between calcium binding sites in the C-terminal signature domain and the N-modules of thrombospondin-1 that regulates ligand binding and functional activities of the N-modules.

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Section: Effects Of Mabs On Sulfated Glycoconjugate Binding To the N supporting

confidence: 83%

“…The major high affinity heparin-binding site of TSP1 is located in the N module (Dixit et al, 1984;Yu et al, 2000). None of these TSP1 antibodies inhibited TSP1 binding to heparin (Fig.…”

Section: Effects Of Mabs On Sulfated Glycoconjugate Binding To the N mentioning

confidence: 99%

Calcium indirectly regulates immunochemical reactivity and functional activities of the N-domain of thrombospondin-1

et al. 2008

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“…Binding of TSP by S. aureus Cowan 1 was partially inhibited by fructose and galactose, but not by mannose, similar to the previous studies of TSP binding by enterococci [16]. Despite the fact that the monosaccharides did not inhibit the binding of TSP to S. epidermidis J9P, carbohydrate-mediated interaction cannot be excluded, as the biological behaviour of the carbohydrates may depend on their chain length [11]. S. epidermidis strains bound to TSP-coated microtitration wells to varying extents, which suggests that TSP is recognised by bacteria not only in soluble forms but also in its immobilised conformation [33±35].…”

Section: Discussionsupporting

confidence: 86%

“…This was shown by the fact that heparin reduced the binding of TSP to staphylococci by almost 90%. The same amount of hyaluronic acid did not inhibit the binding, which indicated that the interaction was not inhibited by the negative charge alone [11]. The possibility that heparin interfered with the binding molecules on the bacteria may be less likely, because TSP binding by bacteria was not reduced when bacteria were treated with heparin before the addition of TSP, which may be explained by the relatively low af®nity of glycosaminoglycans for staphylococci reported previously [26].…”

Section: Discussionmentioning

confidence: 70%

The N-terminal of thrombospondin-1 is essential for coagulase-negative staphylococcal binding

Yanagisawa

Ljungh

2001

Journal of Medical Microbiology

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Bacterial binding was studied to determine whether thrombospondin-1 (TSP) acts as a ligand in attachment of coagulase-negative staphylococci (CNS). Twenty-®ve of 27 CNS strains bound soluble TSP. Staphylococcus epidermidis J9P bound 125 I-labelled TSP in a dose-dependent manner. Scatchard plot analysis of the binding of TSP by strain J9P revealed two K d values of 6:4 3 10 29 m and 2:9 3 10 28 m. The binding structures of strain J9P were sensitive to protease and were resistant to heat treatment. Unlabelled TSP and recombinant von Willebrand factor inhibited binding of TSP by strain J9P, but other proteins or monosaccharides did not. Heparin inhibited binding of TSP to strain J9P and two other S. epidermidis strains, BD5703 and BD969. Fusion proteins of the type 1 repeats, type 2 repeats, type 3 repeats and C-terminal domain of TSP or the synthetic Arg-Gly-Asp peptide did not inhibit binding of TSP to bacteria. TSP promoted adhesion of S. epidermidis strains when it was immobilised on polymer surfaces. These results indicate that the speci®c interaction between CNS and TSP may contribute to bacterial adhesion on biomaterial surfaces. The N-terminal heparin-binding domain of TSP appears to be the major region for recognition by CNS.

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“…This is consistent with the minimum size (tetrasaccharide) of heparin that can bind to TSPN-1. The affinity of TSPN-1 for heparin increases with the length of the oligosaccharide up to a decasaccharide (16,17). In our early studies, we also discovered a long flexible linker (ϳ35 residues) between the TSPN-1 domain and the helical region that is involved in trimer formation (15).…”

Section: Thrombospondin-1 (Tsp-1)mentioning

confidence: 97%

Heparin-induced cis- and trans-Dimerization Modes of the Thrombospondin-1 N-terminal Domain

Tan

Duquette

Liu

et al. 2008

Journal of Biological Chemistry

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Through its interactions with proteins and proteoglycans, thrombospondin-1 (TSP-1) functions at the interface of the cell membrane and the extracellular matrix to regulate matrix structure and cellular phenotype. We have previously determined the structure of the high affinity heparin-binding domain of TSP-1, designated TSPN-1, in association with the synthetic heparin, Arixtra. To establish that the binding of TSPN-1 to Arixtra is representative of the association with naturally occurring heparins, we have determined the structures of TSPN-1 in complex with heparin oligosaccharides containing eight (dp8) and ten (dp10) subunits, by x-ray crystallography. We have found that dp8 and dp10 bind to TSPN-1 in a manner similar to Arixtra and that dp8 and dp10 induce the formation of trans and cis TSPN-1 dimers, respectively. In silico docking calculations partnered with our crystal structures support the importance of arginine residues in positions 29, 42, and 77 in binding sulfate groups of the dp8 and dp10 forms of heparin. The ability of several TSPN-1 domains to bind to glycosaminoglycans simultaneously probably increases the affinity of binding through multivalent interactions. The formation of cis and trans dimers of the TSPN-1 domain with relatively short segments of heparin further enhances the ability of TSP-1 to participate in high affinity binding to glycosaminoglycans. Dimer formation may also involve TSPN-1 domains from two separate TSP-1 molecules. This association would enable glycosaminoglycans to cluster TSP-1. Thrombospondin-1 (TSP-1)4 is a secreted glycoprotein that functions during the tissue remodeling that is associated with development, wound healing, synaptogenesis, angiogenesis, and cancer. Through its interactions with proteins and proteoglycans, TSP-1 functions at the interface of the cell membrane and the extracellular matrix to regulate matrix structure and cellular behavior. The N-terminal domain of TSP-1 (TSPN-1) plays an integral role in the interaction of TSP-1 with other secreted and transmembrane proteins (1, 2). TSPN-1 contains binding sites for 1) glycosaminoglycans, 2) low density lipoprotein receptor-related protein-1, 3) various integrins, 4) calreticulin, and 5) fibrinogen (2). ␤1 integrins that contain the ␣3, ␣4, ␣6, and ␣9 subunits have all been reported to interact with TSPN-1 (3-6). The glycosaminoglycan-binding site is involved in the association of TSP-1 with syndecan-1, -3, and -4, perlecan, decorin, and other proteoglycans (7). In some cases, the TSPN-1 domain may also interact with the core protein (8). TSPN-1 has been shown to be required for the uptake of TSP-1 through a mechanism that involves proteoglycans and lipoprotein receptor-related protein-1 (9). Because proteins, such as matrix metalloproteinases and vascular endothelial cell growth factor, bind to TSP-1, it is possible that they are taken up along with this protein (1, 10). The regulation of matrix metalloproteinases and vascular endothelial cell growth factor levels by this mechanism can affect angiogene...

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Specificities of Heparin-binding Sites from the Amino-Terminus and Type 1 Repeats of Thrombospondin-1

Cited by 28 publications

References 61 publications

Calcium indirectly regulates immunochemical reactivity and functional activities of the N-domain of thrombospondin-1

Calcium indirectly regulates immunochemical reactivity and functional activities of the N-domain of thrombospondin-1

The N-terminal of thrombospondin-1 is essential for coagulase-negative staphylococcal binding

Heparin-induced cis- and trans-Dimerization Modes of the Thrombospondin-1 N-terminal Domain

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