DNA accelerates the inhibition of human cathepsin V by serpins

Chee Ong Poh, Sheena McGowan, Mary C. Pearce, James A. Irving, Wan Ting Kan, Sergei A. Grigoryev, Boris Turk, Gary A. Silverman, Klaudia Brix, Stephen P. Bottomley, James C. Whisstock, Robert N. Pike

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32 Scopus citations

Abstract

A balance between proteolytic activity and protease inhibition is crucial to the appropriate function of many biological processes. There is mounting evidence for the presence of both papain-like cysteine proteases and serpins with a corresponding inhibitory activity in the nucleus. Well characterized examples of cofactors fine tuning serpin activity in the extracellular milieu are known, but such modulation has not been studied for protease-serpin interactions within the cell. Accordingly, we present an investigation into the effect of a DNA-rich environment on the interaction between model serpins (MENT and SCCA-1), cysteine proteases (human cathepsin V and human cathepsin L), and cystatin A. DNA was indeed found to accelerate the rate at which MENT inhibited cathepsin V, a human orthologue of mammalian cathepsin L, up to 50-fold, but unexpectedly this effect was primarily effected via the protease and secondarily by the recruitment of the DNA as a "template" onto which cathepsin V and MENT are bound. Notably, the protease-mediated effect was found to correspond both with an altered substrate turnover and a conformational change within the protease. Consistent with this, cystatin inhibition, which relies on occlusion of the active site rather than the substrate-like behavior ofserpins, was unaltered by DNA. This represents the first example of modulation of serpin inhibition of cysteine proteases by a cofactor and reveals a mechanism for differential regulation of cathepsin proteolytic activity in a DNA-rich environment.

Original languageEnglish (US)
Pages (from-to)36980-36986
Number of pages7
JournalJournal of Biological Chemistry
Volume282
Issue number51
DOIs
StatePublished - Dec 21 2007

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Poh, C. O., McGowan, S., Pearce, M. C., Irving, J. A., Kan, W. T., Grigoryev, S. A., Turk, B., Silverman, G. A., Brix, K., Bottomley, S. P., Whisstock, J. C., & Pike, R. N. (2007). DNA accelerates the inhibition of human cathepsin V by serpins. Journal of Biological Chemistry, 282(51), 36980-36986. https://doi.org/10.1074/jbc.M706991200