Heparan interactions

The activation of a chemokine receptor is more complex than the traditional agonist-receptor paradigm. For example, chemokine activity is mediated by GAGs (heparin, heparan, and heparin sulfate chondroitin sulfate and dermatan sulfate) at various sites during the chemotactic process. Chemokines released by tissue injury, infection, or inflammation activate adjacent endothelial cells and induce rolling and extravasation of leukocytes. These interactions between... 

Valenzuela-Femandez A, Palanche T, Amara A, et al. Optimal inhibition of X4 HIV isolates by the CXC chemokine stromal cell-derived factor 1 alpha requires interaction with cell surface heparan sulfate proteoglycans. J Biol Chem 2001 276(28) 26550-26558. 

Fleckenstein, J. M., Holland, J. T., and Hasty, D. L. (2002). Interaction of an outer membrane protein of enterotoxigenic Escherichia coli with cell surface heparan sulfate proteoglycans. Infect. Immun. 70,1530-1537. 

It is likely that the predominantly positively charged amino acids of TAT and other CPPs will interact with anionic components on the surface of the cell membrane (85). This idea is supported by the observation that cell association with CPP liposomes in glycosaminoglycan-deficient Chinese hamster ovary (CHO) cells is greatly reduced and is competitively inhibited by the presence of heparin (88,93). Furthermore, the removal of the heparan sulfate chains by the action of glycosaminoglycan lyase also suppressed the transduction of the TAT protein (94). 

Type I collagen can interact with various other molecules in the extracellular matrix and on the cell surface. Cell receptors of type I collagen have been identified and include the heterodimeric integrin family receptors, ctl, 0 2, olO, and ol 1, especially o2/3l, the receptor tyrosine kinase discoidin domain receptor (DDR), and the heparan sulfate membrane proteoglycan syndecan family... 

Fig. 4 Interaction of basic FGF on heparan sulfate PG (1) and free GAG (2) induces FGFR dimerization, leading to tyrosine kinase (TK) activation and signal transduction.

Interactions can also be studied at the surface of a coated capillary wall. One binding partner is first immobilized on the capillary wall. As a result of the affinity of the second binding partner, the analyte will be delayed, compared with migration times observed in an untreated capillary. Based on this approach, modified capillaries have been prepared and used successfully to study polysaccharide-protein interactions as well as affinity separations. Coating of the capillary wall with heparin and heparan sulfate has been used to determine the affinity of these polysaccharides for synthetic heparin-binding peptides different only in the stereochemistry of a single... 

JR Fromm, RE Hileman, JM Weiler, RJ Linhardt. Interaction of FGF-1 and related peptides with heparan sulfate and its oligosaccharides. Arch Biochem Biophys 346 252-262, 1997. 

Heparinoid polysaccharides such as heparan sul te and heparin are able to interact with numerous proteins and influence vital biological processes. Heparinoid mimetics were prepared to reduce the structural complexity of heparinoids and to obtain selectivities. This artide summarizes the development of heparinoid mimetics of different classes including representative syntheses and biological activities. Largely simplified compounds with regard to structure and synthetic access are described which maintain or exceed the activity of heparinoid polysaccharides. One of the recipes to increase binding or modify pharmacokinetic parameters was the introduction of hydrophobic groups. 

In keeping with a high amount of non-ionic contact in the bFGF/heparin interaction is the recent and interesting finding that non-sulfated heparan-derived... 

Coombe, D. R. and Kett, W. C. (2005). Heparan sulfate-protein interactions Therapeutic potential through structure-function insights. Cell. Mol. Life Sci. 62, 410-424. 

FIGURE 7-28 Four types of protein interactions with S domains of heparan sulfate. 

The high density of negative charges in heparan sulfate brings positively charged molecules of lipoprotein lipase into the vicinity and holds them by electrostatic interactions as well as by sequence-specific interactions with S domains. Such interactions are also central in the first step in the entry of certain viruses (such as herpes simplex viruses HSV-1 and HSV-2) into cells. 

Proteoglycans bind to a variety of different proteins and polysaccharides. For example, the large extracellular matrix protein tenascin, which is important to adhesion, cell migration, and proliferation, binds to chondroitin sulfate proteoglycans such as neurocan.225 Syndecan, a transmembrane proteoglycan, carries both chondroitin and heparan sulfate chains, enabling it to interact with a variety of proteins that mediate cell-matrix adhesion.185... 

Kawashima, H., Watanabe, N., Hirose, M., Sun, X., Atarashi, K., Kimura, T., Shikata, K., Matsuda, M., Ogawa, D., Heljasvaara, R., Rehn, M., Pihlajaniemi, T., and Miyasaka, M. (2003). Collagen XVIII, a basement membrane heparan sulfate proteoglycan, interacts with L-selectin and monocyte chemoattractant protein-1. / Biol. Chem. 278, 13069-13076. 

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