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Journal of Biochemistry Advance Access originally published online on December 2, 2008
Journal of Biochemistry 2009 145(2):217-227; doi:10.1093/jb/mvn160
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© The Authors 2008. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved

Inhibition of the 20S Proteosome by a Protein Proteinase Inhibitor: Evidence That a Natural Serine Proteinase Inhibitor Can Inhibit a Threonine Proteinase

Kimihiko Yabe and Takehiko Koide*

Department of Life Science, Graduate School of Life Science, University of Hyogo, Harima Science Garden City, Hyogo 678-1297, Japan

*To whom correspondence should be addressed. Tel: +81-791-58-0212, Fax: +81-791-58-0219, E-mail: koide{at}sci.u-hyogo.ac.jp

Received November 1, 2008; Accepted November 19, 2008


  Abstract

The 20S proteasome (20S) is an intracellular threonine proteinase (Mr 750,000) that plays important roles in many cellular regulations. Several synthetic peptide inhibitors and bacteria-derived inhibitors such as lactacystin and epoxomicin have been identified as potent proteasome inhibitors. However, essentially no protein proteinase inhibitor has been characterized. By examining several small size protein proteinase inhibitors, we found that a well-known serine proteinase inhibitor from bovine pancreas, basic pancreatic trypsin inhibitor (BPTI), inhibits the 20S in vitro and ex vivo. Inhibition of the 20S by BPTI was time- and concentration-dependent, and stoichiometric. To inhibit the 20S activity, BPTI needs to enter into the interior of the 20S molecule. The molar ratio of BPTI to the 20S in the complex was estimated as approximately six BPTI to one 20S, thereby two sets of three peptidase activities (trypsin-like, chymotrypsin-like and caspase-like) of the 20S were all inhibited. These results indicate that an entrance hole to the 20S formed by seven {alpha}-subunits is sufficiently large for BPTI to enter. This report is essentially the initial description of the inhibition of a threonine proteinase by a protein serine proteinase inhibitor, suggesting a common mechanism of inhibition between serine and threonine proteinases by a natural protein proteinase inhibitor.

Key Words: 20S proteasome, {alpha}1-antitrypsin, BPTI, cross-class inhibition, proteinase inhibitor

Abbreviations: 20S, 20S proteasome; {alpha}1-AT, {alpha}1-antitrypsin; BBI, soybean Bowman-Birk inhibitor; BPTI, bovine pancreatic trypsin inhibitor; CPTI-II, Cucurbita pepo trypsin inhibitor II; DTT, dithiothreitol; ERAD, ER-associated degradation; LLE, carbobenzoxy-Leu-Leu-Glu-MCA; LLVY, succinyl-Leu-Leu-Val-Tyr-MCA; LRR, t-buthyloxycarbonyl-Leu-Arg-Arg-MCA; MCA, 4-methyl-coumaryl-7-amide; MCTI-I, Momordica charantia trypsin inhibitor I; MG132, carbobenzoxy-leucyl-leucyl-leucinal; NHK, null Hong Kong-type variant of {alpha}1-antitrypsin; SFTI-I, sunflower trypsin inhibitor-I; SKLP, Streptomyces killer toxin-like protein


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