Hai1

HAI-1 is classed as a Kunitz-type serine protease inhibitor due to the similarity it shares with this family of inhibitors in the Kunitz domains residue regions 250-300 and 375-425. The primary HAI-1 translation product is 66 kDa, made up of 513 amino acid residues, and is composed of an NH2-terminal putative signal peptide (1-35 residues), Kunitz domain 1 (250-300 residues), and Kunitz domain 2 (375-25 residues). The region between these Kunitz domains (319-353 residues) shares a high similarity to the low-density lipoprotein (LDL) receptors binding domain. This LDL receptor-like domain, absent in HAI-2, contains a negatively charged domain, the reason for which is unknown, although it may aid in formation of a protease inhibitor complex during the inhibition of HGFA, due to the fact that the HGFA precursor has a high affinity for negatively charged substances. There is also a transmembrane domain and a hydrophobic region at the COOH-terminal end (91, 104) (Figure 4).

Shimomura et al. (123) identified several new soluble forms of HAI-1. These soluble forms differ in form depending upon their site of cleavage, as the primary translation product contains multiple sites for proteolytic processing, resulting in two different sizes of HAI-1. Importantly, these forms of HAI-1 also possess the ability to inhibit the activity of other serine proteases, such as plasmin and matriptase (109). HAI-1 also plays role in plasminogen activator cascade through its regulation of matriptase action (124). The presence of a hydrophobic sequence in the COOH-terminal of the primary translation products, of both HAI-1 and HAI-2, suggests that they are produced in a membrane-associated form, and then proteolytically cleaved into a truncated form and secreted into the extracellular environment (92). This transmembrane associated form reveals multiple sites for proteolytic processing, which has resulted in production of two major secreted forms of 40 and 58kDa (123). The 58kDa form contains both Kunitz domains, whereas the 40kDa from only contains the first Kunitz domain (105, 122). There are at least two proteases, one of which is a metalloproteinase, which can cleave the sites to release these soluble forms of HAI-1, however, presently the factors responsible for shedding of the HAI's is unclear.

HAI-1 is very potent inhibitor of matriptase, HGFA, and trypsin, specifically due to the action of the first Kunitz domain (98, 108, 125). While Kunitz domain 1 is known to possess inhibitory action against HGFA and matriptase, the inhibitory targets of the second Kunitz domain are unknown at present.

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