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Structures of human proteinase 3 and neutrophil elastase--so similar yet so different.

Authors
Type
Published Article
Journal
FEBS Journal
Publisher
Wiley (Blackwell Publishing)
Publication Date
May 13, 2010
Volume
277
Issue
10
Pages
2238–2254
Identifiers
DOI: 10.1111/j.1742-4658.2010.07659.x
PMID: 20423453
Source
USPC - SET - SVS
License
White

Abstract

Proteinase 3 and neutrophil elastase are serine proteinases of the polymorphonuclear neutrophils, which are considered to have both similar localization and ligand specificity because of their high sequence similarity. However, recent studies indicate that they might have different and yet complementary physiologic roles. Specifically, proteinase 3 has intracellular specific protein substrates resulting in its involvement in the regulation of intracellular functions such as proliferation or apoptosis. It behaves as a peripheral membrane protein and its membrane expression is a risk factor in chronic inflammatory diseases. Moreover, in contrast to human neutrophil elastase, proteinase 3 is the preferred target antigen in Wegener's granulomatosis, a particular type of vasculitis. We review the structural basis for the different ligand specificities and membrane binding mechanisms of both enzymes, as well as the putative anti-neutrophil cytoplasm autoantibody epitopes on human neutrophil elastase 3. We also address the differences existing between murine and human enzymes, and their consequences with respect to the development of animal models for the study of human proteinase 3-related pathologies. By integrating the functional and the structural data, we assemble many pieces of a complicated puzzle to provide a new perspective on the structure-function relationship of human proteinase 3 and its interaction with membrane, partner proteins or cleavable substrates. Hence, precise and meticulous structural studies are essential tools for the rational design of specific proteinase 3 substrates or competitive ligands that modulate its activities.

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