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

May Al-Khunaizi, Cliff J. Luke, Yuko S. Askew, Stephen C. Pak, David J. Askew, Sule Cataltepe, David Miller, David R. Mills, Christopher Tsu, Dieter Brömme, James A. Irving, James C. Whisstock, Gary A. Silverman

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


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 > 104 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.

Original languageEnglish
Pages (from-to)3189-3199
Number of pages11
Issue number9
StatePublished - Mar 5 2002


Dive into the research topics of 'The serpin SQN-5 is a dual mechanistic-class inhibitor of serine and cysteine proteinases'. Together they form a unique fingerprint.

Cite this