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Tania Aaquist Ammitzbøll

The autolysis of human HtrA1 is governed by the redox state of its N-terminal domain

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Human HtrA1 (high-temperature requirement protein A1) belongs to a conserved family of serine proteases involved in protein quality control and cell fate. The homotrimeric ubiquitously expressed protease has chymotrypsin-like specificity and primarily targets hydrophobic stretches in selected or misfolded substrate proteins. In addition, the enzyme is capable of exerting autolytic activity removing the N-terminal insulin-like growth factor binding protein (IGFBP)/Kazal-like tandem motif without affecting the protease activity. In this study, we have addressed the mechanism governing the autolytic activity and find that it depends on the integrity of the disulphide bonds in the N-terminal IGFBP/Kazal-like domain. The specificity of the autolytic cleavage reveals a high preference for cysteine in the P1 position of HtrA1, explaining the lack of autolysis prior to disulphide reduction. Significantly, the disulphides were reduced by thioredoxin, suggesting that autolysis of HtrA1 in vivo is linked to the endogenous redox balance and that the N-terminal domain acts as a redox-sensing switch.

Original languageEnglish
JournalBiochemistry
Volume53
Issue23
Pages (from-to)3851-3857
Number of pages7
ISSN0006-2960
DOIs
Publication statusPublished - 20 May 2014

Bibliographical note

This work was supported by grants from the Danish National Research Foundation, the Danish Research Council for Strategic Research/Natural Sciences, and the National Eye Institute (R01 EY012712)

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