Serine Protease Inhibitors - Localization and Roles

Localization and Roles

Approximately two-thirds of human serpins perform extracellular roles. For example, extracellular serpins regulate the proteolytic cascades central to blood clotting (antithrombin), the inflammatory response (antitrypsin, antichymotrypsin, and C1 inhibitor) and tissue remodeling (PAI-1). Non-inhibitory extracellular serpins also perform important roles. Thyroxine-binding globulin and cortisol-binding globulin transport the sterol hormones thyroxine and cortisol, respectively (Figure 3). The protease renin cleaves off a ten-amino acid N-terminal peptide from angiotensinogen to produce the peptide hormone angiotensin I. Table 1 provides a brief summary of human serpin function, as well as some of the diseases that result from serpin deficiency.

The first Intracellular members of the serpin superfamily were identified in the early 1990s. As all nine serpins in Caenorhabditis elegans lack signal sequences, they are probably intracellular. Based upon these data it seems likely that the ancestral serpin to human serpins was an intracellular molecule.

The protease targets of intracellular inhibitory serpins have been more difficult to identify. Characterization is complicated by the observation that many of these molecules appear to perform overlapping roles. Further many human serpins lack precise functional equivalents in model organisms such as the mouse. An important function of intracellular serpins may be to protect against the inappropriate activity of proteases inside the cell. For example, one of the best-characterised human intracellular serpins is SERPINB9, which inhibits the cytotoxic granule protease granzyme B. In doing so, SERPINB9 may protect against inadvertent release of granzyme B and premature or unwanted activation of cell death pathways.

Intracellular serpins also perform roles distinct from protease inhibition. For example, maspin, a non-inhibitory serpin, is important for preventing metastasis in breast and prostate cancers. Another example is the avian nuclear cysteine protease inhibitor MENT, which acts as a chromatin remodelling molecule in avian red blood cells.

Phylogenetic studies show that most intracellular serpins belong to a single clade (see Table 1). Exceptions include the non-inhibitory heat shock serpin HSP47, which is a chaperone essential for proper folding of collagen, and cycles between the cis-Golgi and the endoplasmic reticulum.