Kunitz-type Bauhinia bauhinioides inhibitors devoid of disulfide bridges: isolation of the cDNAs, heterologous expression and structural studies

Biol Chem. 2005 Jun;386(6):561-8. doi: 10.1515/BC.2005.066.

Abstract

Bauhinia bauhinoides cruzipain inhibitor (BbCI) and Bauhinia bauhinioides kallikrein inhibitor (BbKI) are cysteine and serine proteinase inhibitors structurally homologous to plant Kunitz-type inhibitors, but are devoid of disulfide bridges. Based on cDNA sequences, we found that BbKI and BbCI are initially synthesized as a prepropeptide comprising an N-terminal signal peptide (19 residues), the mature protein (164 residues) and a C-terminal targeting peptide (10 residues). Partial cDNAs encoding the mature enzymes plus N-terminal His-tags and thrombin cleavage sites were expressed in E. coli and the soluble proteins were purified by one-step nickel affinity chromatography. After thrombin cleavage, both proteins exhibited potent inhibitory activities toward their cognate proteinases like the wild-type proteins. BbCI inhibits human neutrophil elastase ( K i(app) 5.3 nM), porcine pancreatic elastase ( K i(app) 40 nM), cathepsin G ( K i(app) 160 nM) and the cysteine proteinases cruzipain ( K i(app) 1.2 nM), cruzain ( K i(app) 0.3 nM) and cathepsin L ( K i(app) 2.2 nM), while BbKI strongly inhibits plasma kallikrein ( K i(app) 2.4 nM) and plasmin ( K i(app) 33 nM). Circular dichroism spectra of BbCI and BbKI were in agreement with the beta-trefoil fold described for Kunitz inhibitors. The inhibitory potency of both BbCI- and BbKI-type inhibitors suggests that other, non-covalent interactions may compensate for the lack of disulfide bridges.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Bauhinia
  • Binding Sites
  • Cathepsin L
  • Cathepsins / antagonists & inhibitors
  • Circular Dichroism
  • Cloning, Molecular
  • Cysteine Endopeptidases / metabolism
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / genetics*
  • Cysteine Proteinase Inhibitors / metabolism
  • Cysteine Proteinase Inhibitors / pharmacology
  • DNA, Complementary / isolation & purification
  • DNA, Plant / analysis
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Molecular Sequence Data
  • Peptides
  • Plant Proteins / chemistry
  • Plant Proteins / genetics*
  • Plant Proteins / metabolism
  • Plant Proteins / pharmacology
  • Protozoan Proteins
  • RNA, Plant / analysis
  • Recombinant Proteins / pharmacology
  • Seeds / chemistry
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / genetics*
  • Serine Proteinase Inhibitors / metabolism
  • Serine Proteinase Inhibitors / pharmacology

Substances

  • BbCI protein, Bauhinia bauhinoides
  • BbKI protein, Bauhinia bauhinioides
  • Cysteine Proteinase Inhibitors
  • DNA, Complementary
  • DNA, Plant
  • Kunitz-type protease inhibitor, plant
  • Peptides
  • Plant Proteins
  • Protozoan Proteins
  • RNA, Plant
  • Recombinant Proteins
  • Serine Proteinase Inhibitors
  • Cathepsins
  • Cysteine Endopeptidases
  • CTSL protein, human
  • Cathepsin L
  • cruzipain