Heparin-induced cis- and trans-dimerization modes of the thrombospondin-1 N-terminal domain.

2.50
Hdl Handle:
http://hdl.handle.net/10541/66173
Title:
Heparin-induced cis- and trans-dimerization modes of the thrombospondin-1 N-terminal domain.
Authors:
Tan, Kemin; Duquette, Mark; Liu, Jin-Huan; Shanmugasundaram, Kumaran; Joachimiak, Andrzej; Gallagher, John T; Rigby, Alan C; Wang, Jia-huai; Lawler, Jack
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.
Affiliation:
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Citation:
Heparin-induced cis- and trans-dimerization modes of the thrombospondin-1 N-terminal domain. 2008, 283 (7):3932-41 J. Biol. Chem.
Journal:
The Journal of Biological Chemistry
Issue Date:
15-Feb-2008
URI:
http://hdl.handle.net/10541/66173
DOI:
10.1074/jbc.M705203200
PubMed ID:
18065761
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
All Paterson Institute for Cancer Research; Medical Oncology

Full metadata record

DC FieldValue Language
dc.contributor.authorTan, Kemin-
dc.contributor.authorDuquette, Mark-
dc.contributor.authorLiu, Jin-Huan-
dc.contributor.authorShanmugasundaram, Kumaran-
dc.contributor.authorJoachimiak, Andrzej-
dc.contributor.authorGallagher, John T-
dc.contributor.authorRigby, Alan C-
dc.contributor.authorWang, Jia-huai-
dc.contributor.authorLawler, Jack-
dc.date.accessioned2009-04-24T09:18:11Z-
dc.date.available2009-04-24T09:18:11Z-
dc.date.issued2008-02-15-
dc.identifier.citationHeparin-induced cis- and trans-dimerization modes of the thrombospondin-1 N-terminal domain. 2008, 283 (7):3932-41 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid18065761-
dc.identifier.doi10.1074/jbc.M705203200-
dc.identifier.urihttp://hdl.handle.net/10541/66173-
dc.description.abstractThrough 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.en
dc.language.isoenen
dc.subject.meshChromatography, Gel-
dc.subject.meshCrystallization-
dc.subject.meshCrystallography, X-Ray-
dc.subject.meshDimerization-
dc.subject.meshHeparin-
dc.subject.meshHumans-
dc.subject.meshModels, Molecular-
dc.subject.meshProtein Conformation-
dc.subject.meshRecombinant Proteins-
dc.subject.meshThrombospondin 1-
dc.titleHeparin-induced cis- and trans-dimerization modes of the thrombospondin-1 N-terminal domain.en
dc.typeArticleen
dc.contributor.departmentDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.en
dc.identifier.journalThe Journal of Biological Chemistryen

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