Abstract
SLPI (secretory leukocyte protease inhibitor) is a 107-residue non-glycosylated protease inhibitor, which inhibits a wide range of serine proteases, trypsin, chymotrypsin, neutrophil elastase, chymase and cathepsin G. X-ray crystallographic analyses have shown that SLPI comprises two separate domains of similar architecture [Grütter, Fendrich, Huber & Bode (1988), EMBO J. 7, 345-351] and the C-terminal domain interacts with bovine alpha-chymotrypsin. In order to understand SLPI's multiple functions against various serine proteases, the complex HNE (human neutrophil elastase) has been co-crystallized with 1/2SLPI (recombinant C-terminal domain of SLPI; Arg58-Ala107), which has a biological activity similar to full SLPI. The 1/2SLPI and HNE complex structure was solved at 1.7 A resolution, and compared with the interaction mechanism of elafin, which is a specific inhibitor of elastase. It was found that P1 Leu72i and six hydrogen bonds between the main chains in the primary contact region have sufficient ability to inhibit HNE and PPE (porcine pancreatic elastase), and P5 Tyr68i is important in increasing the selectivity of 1/2SLPI against HNE. The mechanisms of the functions of SLPI are relatively unknown, but the current study could help understand the selectivity of SLPI against HNE and PPE.
Highlights
The SLPI similar domain motif is present in several other secreted proteins called the WAP four-disulfide core (WFDC) domain family
There are a small number of intra-hydrogen bonds and electrostatic interactions in the 1/2SLPI structure (Fig. 1b)
No mainchain–main-chain hydrogen bond is formed between the two parallel strands A and C, and one hydrogen bond is formed between strands B and D
Summary
The SLPI (secretory leukocyte protease inhibitor) similar domain motif is present in several other secreted proteins called the WAP four-disulfide core (WFDC) domain family. The X-ray structure shows that elafin inhibits PPE in a similar way as the SLPI C-terminal domain (Tsunemi et al, 1996). How are these differences in selectivity against serine proteases between SLPI and elafin caused? Elafin and SLPI have multiple important roles both in normal homeostasis and at the site of inflammation These include anti-protease and anti-microbial activity as well as modulation of the response to LPS stimulation. Both are members of larger families of proteins secreted predominantly at mucosal sites and are modulated under multiple pathological conditions, and control the conditioning of the innate immune system. We report here the details of their interactions with 1/2SLPI and HNE and describe the comparison with elafin:PPE complexes (Tsunemi et al, 1996)
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