Structural basis for the kexin-like serine protease from Aeromonas sobria as sepsis-causing factor.
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.
Kobayashi
Hidetomo
H
Laboratory of Molecular Microbiological Science, Faculty of Pharmaceutical Sciences, Hiroshima International University, Hiro-Koshingai, Kure, Hiroshima 737-0112, Japan.
Utsunomiya
Hiroko
H
Yamanaka
Hiroyasu
H
Sei
Yoshihisa
Y
Katunuma
Nobuhiko
N
Okamoto
Keinosuke
K
Tsuge
Hideaki
H
D000333:Aeromonas / Q000201:enzymology*; D000595:Amino Acid Sequence; D000985:Antisepsis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D045683:Furin / Q000737:chemistry; D013058:Mass Spectrometry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D018805:Sepsis / Q000382:microbiology*; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity; D020860:Subtilisin / Q000737:chemistry; D037521:Virulence Factors / Q000737:chemistry* / Q000378:metabolism*
D037521:Virulence Factors; D012697:Serine Endopeptidases; D020860:Subtilisin; D045683:Furin