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J. Biol. Chem., Vol. 283, Issue 7, 3932-3941, February 15, 2008

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

From the ^aDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, the ^dDivision of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, the Departments of ^bMedicine, ⁱPathology, ^gPediatrics, and ^hBiological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, the ^cMidwest Center for Structural Gemomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, the ^fCancer Research UK and Department of Medical Oncology, University of Manchester, Christie Hospital National Health Service Trust, Wilmslow Road, Manchester M20 4BX, and the ^eDivision of Molecular and Vascular Medicine, Department of Medicine, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

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.

Received for publication, June 25, 2007 , and in revised form, November 21, 2007.

^* This work was support by Grants HL49081, HL48675, and HL68003 from NHLBI, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (code 2OUH and 2OUJ) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

¹ To whom correspondence may be addressed: Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215. Tel.: 617-667-0637; Fax: 617-667-2913; E-mail: arigby{at}bidmc.harvard.edu. ² To whom correspondence may be addressed: Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St., Rm. SM-1036, Boston, MA 02115. Tel.: 617-632-3983; Fax: 617-632-4393; E-mail: jwang{at}red.dfci.harvard.edu. ³ To whom correspondence may be addressed: Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Ave., Boston, MA 02215. Tel.: 617-667-1694; Fax: 617-667-3591; E-mail: jlawler{at}bidmc.harvard.edu.

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