The anaerobic bacterium Aeromonas sobria is known to cause potentially lethal
septic shock. We recently proposed that A. sobria
serine protease (ASP) is a
sepsis-related factor that induces vascular leakage, reductions in blood pressure via
kinin release, and clotting via activation of
prothrombin. ASP preferentially cleaves
peptide bonds that follow dibasic
amino acid residues, as do Kex2 (Saccharomyces cerevisiae
serine protease) and
furin, which are representative kexin family
proteases. Here, we revealed the crystal structure of ASP at 1.65 A resolution using the multiple isomorphous replacement method with anomalous scattering. Although the overall structure of ASP resembles that of Kex2, it has a unique extra occluding region close to its active site. Moreover, we found that a nicked ASP variant is cleaved within the occluding region. Nicked ASP shows a greater ability to cleave small
peptide substrates than the native
enzyme. On the other hand, the cleavage pattern for
prekallikrein differs from that of ASP, suggesting the occluding region is important for substrate recognition. The extra occluding region of ASP is unique and could serve as a useful target to facilitate development of novel antisepsis drugs.