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

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...

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Bibliographic Details
Published in:The Journal of biological chemistry 2008-02, Vol.283 (7), p.3932-3941
Main Authors: Tan, Kemin, Duquette, Mark, Liu, Jin-huan, Shanmugasundaram, Kumaran, Joachimiak, Andrzej, Gallagher, John T., Rigby, Alan C., Wang, Jia-huai, Lawler, Jack
Format: Article
Language:English
Subjects:
BASIC BIOLOGICAL SCIENCES
BLOOD
CATALYTIC EFFECTS
Chromatography, Gel
Crystallization
Crystallography, X-Ray
DIMERIZATION
HEPARIN
Heparin - chemistry
Humans
Models, Molecular
Protein Conformation
Recombinant Proteins - chemistry
Recombinant Proteins - metabolism
Thrombospondin 1 - chemistry
Thrombospondin 1 - metabolism
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M705203200