The structures of the thrombospondin-1 N-terminal domain and its complex with a synthetic pentameric heparin.
The N-terminal domain of thrombospondin-1 (TSPN-1) mediates the protein's interaction with (1) glycosaminoglycans, calreticulin, and integrins during cellular adhesion, (2) low-density lipoprotein receptor-related protein during uptake and clearance, and (3) fibrinogen during platelet aggregation. The crystal structure of TSPN-1 to 1.8 A resolution is a beta sandwich with 13 antiparallel beta strands and 1 irregular strand-like segment. Unique structural features of the N- and C-terminal regions, and the disulfide bond location, distinguish TSPN-1 from the laminin G domain and other concanavalin A-like lectins/glucanases superfamily members. The crystal structure of the complex of TSPN-1 with heparin indicates that residues R29, R42, and R77 in an extensive positively charged patch at the bottom of the domain specifically associate with the sulfate groups of heparin. The TSPN-1 structure and identified adjacent linker region provide a structural framework for the analysis of the TSPN domain of various molecules, including TSPs, NELLs, many collagens, TSPEAR, and kielin.
Tan
Kemin
K
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Duquette
Mark
M
Liu
Jin-Huan
JH
Zhang
Rongguang
R
Joachimiak
Andrzej
A
Wang
Jia-huai
JH
Lawler
Jack
J
D000595:Amino Acid Sequence; D001665:Binding Sites; D003208:Concanavalin A / Q000737:chemistry; D003460:Crystallization; D018360:Crystallography, X-Ray; D000077425:Fondaparinux; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D011134:Polysaccharides / Q000138:chemical synthesis*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D019700:Thrombospondin 1 / Q000737:chemistry*
D010446:Peptide Fragments; D011134:Polysaccharides; D019700:Thrombospondin 1; D003208:Concanavalin A; D000077425:Fondaparinux