GSBS Student Publications

Title

The serpin SQN-5 is a dual mechanistic-class inhibitor of serine and cysteine proteinases

Student Author(s)

David M. Miller

Date

3-5-2002

Document Type

Article

Medical Subject Headings

Amino Acid Sequence; Animals; Antigens, Neoplasm; Binding, Competitive; Cathepsins; Cysteine Endopeptidases; Humans; Kinetics; Mice; Molecular Sequence Data; Phylogeny; Protease Inhibitors; Sequence Homology, Amino Acid; Serine Endopeptidases; Serpins

Disciplines

Biochemistry, Biophysics, and Structural Biology | Life Sciences | Medicine and Health Sciences

Abstract

SQN-5 is a mouse serpin that is highly similar to the human serpins SCCA1 (SERPINB3) and SCCA2 (SERPINB4). Previous studies characterizing the biochemical activity of SQN-5 showed that this serpin, like SCCA2, inhibited the chymotrypsin-like enzymes mast cell chymase and cathepsin G. Using an expanded panel of papain-like cysteine proteinases, we now show that SQN-5, like SCCA1, inhibited cathepsins K, L, S, and V but not cathepsin B or H. These interactions were characterized by stoichiometries of inhibition that were nearly 1:1 and second-order rate constants of >10(4) M(-1) s(-1). Reactive site loop (RSL) cleavage analysis showed that SQN-5 employed different reactive centers to neutralize the serine and cysteine proteinases. To our knowledge, this is the first serpin that serves as a dual inhibitor of both chymotrypsin-like serine and the papain-like cysteine proteinases by employing an RSL-dependent inhibitory mechanism. The ability of serpins to inhibit both serine and/or papain-like cysteine proteinases may not be a recent event in mammalian evolution. Phylogenetic studies suggested that the SCCA and SQN genes evolved from a common ancestor approximately 250-280 million years ago. When the fact that mammals and birds diverged approximately 310 million years ago is considered, an ancestral SCCA/SQN-like serpin with dual inhibitory activity may be present in many mammalian genomes.

Rights and Permissions

Citation: Biochemistry. 2002 Mar 5;41(9):3189-99.

Related Resources

Link to article in PubMed

Journal Title

Biochemistry

PubMed ID

11863458