2OUH

Crystal structure of the Thrombospondin-1 N-terminal domain in complex with fractionated Heparin DP10

Summary for 2OUH

• Entry DOI: 10.2210/pdb2ouh/pdb
• Related: 1Z78 1ZA4 2OUJ
• Descriptor: Thrombospondin-1, SULFATE ION (3 entities in total)
• Functional Keywords: tsp-1, tspn-1, hbd, fractionated heparin, dp10, cell adhesion
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 55688.58

Authors

Tan, K.,Joachimiak, A.,Wang, J.,Lawler, J. (deposition date: 2007-02-11, release date: 2008-01-08, Last modification date: 2024-10-09)

Primary citation

Tan, K.,Duquette, M.,Liu, J.H.,Shanmugasundaram, K.,Joachimiak, A.,Gallagher, J.T.,Rigby, A.C.,Wang, J.H.,Lawler, J.
Heparin-induced cis- and trans-Dimerization Modes of the Thrombospondin-1 N-terminal Domain.
J.Biol.Chem., 283:3932-3941, 2008

PubMed Abstract: 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.

PubMed: 18065761
DOI: 10.1074/jbc.M705203200

Experimental method

X-RAY DIFFRACTION (2.4 Å)