Serpin-glycosaminoglycan interactions.

Serpins (serine protease inhibitors) have traditionally been grouped together based on structural homology. They share common structural features of primary sequence, but not all serpins require binding to cofactors in order to achieve maximal protease inhibition. In order to obtain physiologically relevant rates of inhibition of target proteases, some serpins utilize the unbranched sulfated polysaccharide chains known as glycosaminoglycans (GAGs) to enhance inhibition. These GAG-binding serpins include antithrombin (AT), heparin cofactor II (HCII), and protein C inhibitor (PCI). The GAGs heparin and heparan sulfate have been shown to bind AT, HCII, and PCI, while HCII is also able to utilize dermatan sulfate as a cofactor. Other serpins such as PAI-1, kallistatin, and α(1)-antitrypsin also interact with GAGs with different endpoints, some accelerating protease inhibition while others inhibit it. There are many serpins that bind or carry ligands that are unrelated to GAGs, which are described elsewhere in this work. For most GAG-binding serpins, binding of the GAG occurs in a conserved region of the serpin near or involving helix D, with the exception of PCI, which utilizes helix H. The binding of GAG to serpin can lead to a conformational change within the serpin, which can lead to increased or tighter binding to the protease, and can accelerate the rates of inhibition up to 10,000-fold compared to the unbound native serpin. In this chapter, we will discuss three major GAG-binding serpins with known physiological roles in modulating coagulation: AT (SERPINC1), HCII (SERPIND1), and PCI (SERPINA5). We will review methodologies implemented to study the structure of these serpins and those used to study their interactions with GAG's. We discuss novel techniques to examine the serpin-GAG interaction and finally we review the biological roles of these serpins by describing the mouse models used to study them.