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Journal of Biochemistry Advance Access published online on December 2, 2008
Journal of Biochemistry, 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

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

Address correspondence to: Dr. Takehiko Koide, Department of Life Science, Graduate School of Life Science, University of Hyogo, Harima Science Garden City, Hyogo 678-1297, Japan. Phone:++(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. In order 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


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