The N-terminus of thrombospondin: the domain stands apart

Abstract

Thrombospondin 1 (TSP1) was first recognized as a thrombin-sensitive protein associated with platelet membranes. It is secreted by numerous cell types and its expression is predominant in areas of active tissue remodeling. Thrombospondins 1 and 2 are large, trimeric, matricellular proteins, composed of multiple structural motifs which interact with a diverse array of receptors and molecules. Thrombospondin’s capacity to bind multiple receptors renders it multifunctional. The functions of its isolated domains can be overlapping or contradictory. In this review, we focus on the N-terminus of the molecule, first recognized for its strong heparin binding properties and characterized by its susceptibility to proteolytic cleavage from the stalk region of thrombospondin. The N-terminus, called the heparin binding domain (HBD), interacts with a variety of macromolecules including heparan sulfate proteoglycans at the membrane and in the matrix, LDL receptor-related protein (LRP), sulfated glycolipids, calreticulin, and integrins. The HBD mediates endocytosis of thrombospondin. It functions both as a soluble and an insoluble modulator of cell adhesion and motility. In contrast to thrombospondin, the HBD has pro-angiogenic activity. We propose that the HBD of thrombospondins 1 and 2 are found primarily in the cellular microenvironment in conditions of cellular injury, stress and tissue remodeling and that the HBD conveys multiple signals involved in cellular adaptation to injury.

Introduction

In 1978, thrombospondin 1 (TSP1) was first recognized to be a heparin-binding protein by Lawler, Slayter, and Coligan (1978) and in 1984, the localization of this heparin-binding region to the amino-terminus of TSP1 was reported (Dixit, Grant, Santoro, & Frazier, 1984). This amino-terminal domain can be generated by multiple proteases (Dixit et al., 1984; Lawler & Slayter, 1981). The generation of monoclonal antibodies (A2.5, MAII) by the Frazier and Lawler labs (Galvin et al., 1985; Lawler, Derick, Connolly, Chen, & Chao, 1985) was important for modeling of TSP’s domains and for providing initial insights into the function of TSP1 and the N-terminal heparin binding domain (HBD) (Dixit et al., 1985, Galvin et al., 1985). The first functions blocked by antibodies to the HBD were hemagglutination of fixed erythrocytes and agglutination of fixed, activated platelets (Dixit et al., 1985). In the nearly 20 years since these reports, the structure and function of the HBD has been investigated by numerous investigators. One unexpected finding is the diverse array of molecular interactions identified for this domain (Fig. 1). Receptors and molecular binding partners for the HBD as well as in vitro functions of this molecule will be reviewed here.