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

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.

α-Linoleic Acid Enhances the Capacity of α1-Antitrypsin to Inhibit Lipopolysaccharide-Induced IL-1β in Human Blood Neutrophils

“…Neutrophils were then stimulated with 20 ng/mL LPS (Escherichia coli LPS 055:B5, SigmaAldrich) alone or in a combination with 1 mg/mL A1AT-0 or A1AT-LA at 37°C and placed in 5% CO 2 . In parallel, neutrophils were incubated with PBS or LA, A1AT-0 or A1AT-LA alone.…”

“…RNA purity was analyzed on 1% agarose gels. cDNA was synthesized from 1 μg of RNA with RT 2 First Strand kit (Biosciences, Qiagen) and analyzed for expression of NFκB-pathway related genes using Human Angiogenesis RT 2 Profiler PCR Array (Biosciences, Qiagen) according to the manufacturer's protocol. Quantitative real-time PCR was conducted on an ABI 7500 machine (Applied Biosystems).…”

Wnt3a stimulates maturation of impaired neutrophils developed from severe congenital neutropenia patient-derived pluripotent stem cells

“…Approximately 50% of autosomal-dominant SCN cases were shown to have various heterozygous mutations in the gene encoding neutrophil elastase [elastase, neutrophil-expressed (ELANE)] (5, 6), a monomeric, 218-amino acid (25 kDa) chymotryptic serine protease (7) that is synthesized during the early stages of primary granule production in promyelocytes (8,9). However, the mechanism(s) causing impaired neutrophil maturation in SCN patients remains unclear due to the current lack of an appropriate disease model.…”

Inhibitors and Antibody Fragments as Potential Anti-Inflammatory Therapeutics Targeting Neutrophil Proteinase 3 in Human Disease

“…Upon neutrophil activation, an additional amount of PR3 is exposed on the neutrophil cell surface (called induced PR3) (Korkmaz et al, 2009). PR3 exhibits structural and physicochemical properties similar to HNE (Hajjar et al, 2010).…”