Structural basis for the kexin-like serine protease from Aeromonas sobria as sepsis-causing factor

Hidemoto Kobayashi, Hiroko Utsunomiya, Hiroyasu Yamanaka, Yoshihisa Sei, Nobuhiko Katunuma, Keinosuke Okamoto, Hideaki Tsuge

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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 Åresolution 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. More-over, 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.

Original languageEnglish
Pages (from-to)27655-27663
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number40
DOIs
Publication statusPublished - Oct 2 2009

Fingerprint

Aeromonas
Serine Proteases
Sepsis
Diamino Amino Acids
Antisepsis
Prekallikrein
Furin
Peptides
Kinins
Anaerobic Bacteria
Blood pressure
Prothrombin
Substrates
Septic Shock
Yeast
Saccharomyces cerevisiae
Catalytic Domain
Bacteria
Peptide Hydrolases
Crystal structure

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Structural basis for the kexin-like serine protease from Aeromonas sobria as sepsis-causing factor. / Kobayashi, Hidemoto; Utsunomiya, Hiroko; Yamanaka, Hiroyasu; Sei, Yoshihisa; Katunuma, Nobuhiko; Okamoto, Keinosuke; Tsuge, Hideaki.

In: Journal of Biological Chemistry, Vol. 284, No. 40, 02.10.2009, p. 27655-27663.

Research output: Contribution to journalArticle

Kobayashi, H, Utsunomiya, H, Yamanaka, H, Sei, Y, Katunuma, N, Okamoto, K & Tsuge, H 2009, 'Structural basis for the kexin-like serine protease from Aeromonas sobria as sepsis-causing factor', Journal of Biological Chemistry, vol. 284, no. 40, pp. 27655-27663. https://doi.org/10.1074/jbc.M109.006114
Kobayashi, Hidemoto ; Utsunomiya, Hiroko ; Yamanaka, Hiroyasu ; Sei, Yoshihisa ; Katunuma, Nobuhiko ; Okamoto, Keinosuke ; Tsuge, Hideaki. / Structural basis for the kexin-like serine protease from Aeromonas sobria as sepsis-causing factor. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 40. pp. 27655-27663.
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