The serpin SQN-5 is a dual mechanistic-class inhibitor of serine and cysteine proteinases
Biochemistry & Molecular Pharmacology
Biochemistry, Biophysics, and Structural Biology | Life Sciences | Medicine and Health Sciences
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.
DOI of Published Version
Biochemistry. 2002 Mar 5;41(9):3189-99.
Al-Khunaizi, May; Luke, Cliff J.; Askew, Yuko S.; Pak, Stephen C.; Askew, David J.; Cataltepe, Sule; Miller, David M.; Mills, David R.; Tsu, Christopher; Bromme, Dieter; Irving, James A.; Whisstock, James C.; and Silverman, Gary A., "The serpin SQN-5 is a dual mechanistic-class inhibitor of serine and cysteine proteinases" (2002). GSBS Student Publications. 1627.