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The C-D interhelical domain of the serpin plasminogen activator inhibitor-type 2 is required for protection from TNF-
induced apoptosis
Citation
Dickinson, JL and Norris, BJ and Jensen, PH and Antalis, TM, The C-D interhelical domain of the serpin plasminogen activator inhibitor-type 2 is required for protection from TNF- induced apoptosis, Cell Death and Differentiation, 5, (2) pp. 163-171. ISSN 1350-9047 (1998) [Refereed Article]
DOI: doi:10.1038/sj.cdd.4400324
Abstract
The serine proteinase inhibitor (serpin), plasminogen activator inhibitor type 2 (PAI-2), has been reported to inhibit tumor necrosis factor-α (TNF) induced apoptosis. In order to begin to understand the molecular basis for this protection, we have investigated the importance of a structural domain within the PAI-2 molecule, the C-D interhelical region, in mediating the protective effect. The C-D interhelical region is a 33 amino acid insertion which is unique among serpins and has been implicated in transglutaminase catalyzed cross-linking of PAI-2 to cell membranes. We have constructed a mutant of PAI-2 wherein 23 amino acids are deleted from the C-D interhelical region generating a structure predicted to be homologous to the closely related, but non-inhibitory serpin, chicken ovalbumin. The PAI-2Î"65/87 deletion mutant retained inhibitory activity against its known serine proteinase target, urokinase-type plasminogen activator (uPA); however expression of this mutant in HeLa cells failed to protect from TNF-induced apoptosis. Analyses of the cellular distribution of PAI-2 showed that intracellular PAI-2, and not secreted or cell-surface PAI-2, was likely responsible for the observed protection from TNF-induced apoptosis. No evidence was found for specific cross-linking of PAI-2 to the plasma membrane in either control or TNF/cycloheximide treated cells. The data demonstrate that the PAI-2 C-D interhelical domain is functionally important in PAI-2 protection from TNF induced apoptosis and suggest a novel function for the C-D interhelical domain in the protective mechanism.
Item Details
Item Type: | Refereed Article |
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Research Division: | Biomedical and Clinical Sciences |
Research Group: | Medical biochemistry and metabolomics |
Research Field: | Medical biochemistry and metabolomics not elsewhere classified |
Objective Division: | Health |
Objective Group: | Clinical health |
Objective Field: | Clinical health not elsewhere classified |
UTAS Author: | Dickinson, JL (Professor Joanne Dickinson) |
ID Code: | 13875 |
Year Published: | 1998 |
Web of Science® Times Cited: | 56 |
Deposited By: | Menzies Centre |
Deposited On: | 1998-08-01 |
Last Modified: | 2011-08-08 |
Downloads: | 0 |
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