The structural puzzle of how serpin serine proteinase inhibitors work

Ht, Wright

doi:10.1002/bies.950180607

Cited by 64 publications

(49 citation statements)

References 71 publications

(22 reference statements)

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“…In this screen, we identified serpin 2a (spi2a) as a protein with substantially increased expression during BCG infection in vivo (6,7). Serpins are a protein superfamily with conserved structure that regulate both serine and cysteine protease function in diverse processes including coagulation, extracellular matrix degradation, complement activation, fibrinolysis, and apoptosis (8,9). We report here that spi2a is increased Ͼ100-fold not only during in vivo activation of macrophages by BCG but also during infection of mice with Listeria monocytogenes and Salmonella typhimurium.…”

mentioning

confidence: 78%

“…Serpins are a protein superfamily with conserved structure and have been demonstrated to regulate serine and cysteine protease function both extracellularly and intracellularly (8). Serpins have been shown to participate in diverse processes mediated by proteases including complement activation, coagulation, fibrinolysis, extracellular matrix degradation, and apoptosis (9). Although some members of the serpin family, such as OVA and angiotensin, are not functional protease inhibitors (8), spi2a possesses the serpin proximal hinge motif indicative of a functional inhibitor (34) (J.…”

Section: Discussionmentioning

confidence: 99%

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Serpin 2a Is Induced in Activated Macrophages and Conjugates to a Ubiquitin Homolog

Hamerman

Hayashi

Schroeder

et al. 2002

The Journal of Immunology

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After i.p. infection of mice with the intracellular bacterium Mycobacterium bovis bacillus Calmette-Guérin, macrophages recovered from the peritoneal cavity display classical signs of immune activation. We have identified a member of the serine protease inhibitor (serpin) family which is highly induced in macrophages during bacillus Calmette-Guérin infection. Serpin 2a (spi2a) expression is also induced in macrophages in vivo during infection with Salmonella typhimurium and Listeria monocytogenes, and in vitro by a variety of bacteria and bacterial products. The cytokine IFN-γ also induces spi2a expression in macrophages, and this induction is synergistic with bacterial products. We also demonstrate here that a ubiquitin homolog, IFN-stimulated gene of 15-kDa (ISG15), is strongly induced during in vitro and in vivo activation of macrophages and that it conjugates to spi2a in activated macrophages. The ISG15-spi2a conjugates were identified by tandem mass spectrometry and contained spi2a conjugated to either one or two molecules of ISG15. Whereas spi2a was induced by either bacterial products or IFN-γ, ISG15 was induced only by bacterial products. Although many protein targets have been described for ubiquitin conjugation, spi2a is the first ISG15-modified protein to be reported. Macrophage activation is accompanied by the activation of a variety of proteases. It is of interest that a member of the serine protease inhibitor family is concomitantly induced and modified by a ubiquitin-like protein.

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mentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Serpin 2a Is Induced in Activated Macrophages and Conjugates to a Ubiquitin Homolog

Hamerman

Hayashi

Schroeder

et al. 2002

The Journal of Immunology

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“…Its physical properties (2), mechanism (3), and structure (4,5) conform to the general model (6, 7) that has been established for serpins. These inhibitors present a flexible reactive site loop, which is cleaved at a susceptible residue by target proteinase (8,9) to form a highly stable, covalent complex (10,11). As in other serpins (12), the reactive site loop in the cleaved form of ACT is inserted into a preexisting, flexible ␤-sheet (sA) (4), and this cleaved form is stabilized to denaturation relative to the uncleaved native form (2).…”

mentioning

confidence: 99%

Alzheimer's Peptide Aβ1–42 Binds to Two β-Sheets of α1-Antichymotrypsin and Transforms It from Inhibitor to Substrate

Janciauskiene¹,

Rubin²,

Lukacs³

et al. 1998

Journal of Biological Chemistry

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The serpin ␣ 1 -antichymotrypsin is a major component of brain amyloid plaques in Alzheimer's disease. In vitro ␣ 1 -antichymotrypsin interacts with the Alzheimer's amyloid peptide A␤ 1-42 and stimulates both formation and disruption of neurotoxic A␤ 1-42 fibrils in a concentration-dependent manner. We have constructed a new hybrid model of the complex between A␤ 1-42 and ␣ 1 -antichymotrypsin in which both amino and carboxyl sequences of A␤ 1-42 insert into two different ␤-sheets of ␣ 1 -antichymotrypsin. We have tested this model and shown experimentally that full-length and amino-terminal segments of A␤ 1-42 bind to ␣ 1 -antichymotrypsin as predicted. We also show that A␤ 1-42 forms both intraand intermolecular SDS-stable complexes with ␣ 1 -antichymotrypsin and that the binding of A␤ 1-42 to ␣ 1 -antichymotrypsin abolishes the inhibitory activity of the latter and its ability to form stable complex with chymotrypsin. The existence of both inter-as well as intramolecular complexes of A␤ 1-42 explains the nonlinear concentration-dependent effects of ␣ 1 -antichymotrypsin on A␤ 1-42 fibril formation, which we have reinvestigated here over a broad range of A␤ 1-42 :␣ 1 -antichymotrypsin ratios. These data suggest a molecular basis for the distinction between amorphous and fibrillar A␤ 1-42 in vivo. The reciprocal effects of A␤ 1-42 and ␣ 1 -antichymotrypsin could play a role in the etiology of Alzheimer's disease.1 is a serpin serine proteinase inhibitor with specificity for cathepsin and chymotrypsin-like enzymes (1). Its physical properties (2), mechanism (3), and structure (4, 5) conform to the general model (6, 7) that has been established for serpins. These inhibitors present a flexible reactive site loop, which is cleaved at a susceptible residue by target proteinase (8, 9) to form a highly stable, covalent complex (10, 11). As in other serpins (12), the reactive site loop in the cleaved form of ACT is inserted into a preexisting, flexible ␤-sheet (sA) (4), and this cleaved form is stabilized to denaturation relative to the uncleaved native form (2). There is evidence (13, 14) consistent with proposals (10, 11) that insertion of the reactive site loop into sA is a prerequisite for stable proteinase-serpin complex formation. In further support of this, it has been shown that exogenous peptides of restricted sequence can insert into sA of the uncleaved serpin (15-17). These binary peptide⅐serpin complexes are similarly increased in stability to denaturation but have lost inhibitory activity, becoming substrates instead that do not form a stable complex with target proteinase.A possible link between ACT and Alzheimer's disease was established by the observation that ACT occurs in the senile plaques characteristic of this disease (18). Subsequently, it was shown in vitro that ACT can either stimulate formation of the neurotoxic fibrillar form of Alzheimer's peptide A␤ 1-42 (19, 20) or destabilize preformed A␤ 1-40 fibrils (21, 22), depending on the stoichiometry of ACT to A␤. Two models for the binding of A␤...

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“…Serine proteases such as elastase are irreversibly inhibited by the serine protease inhibitor (serpin) Serpina1 and ␣ 2 -macroglobulin (␣ 2 -MG) (28)(29)(30). Serpins belong to a single superfamily with highly conserved secondary structural elements and inhibit their target protease by covalent binding.…”

Section: Discussionmentioning

confidence: 99%

Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization

Pel

Velders

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Here, we report that cytokine-induced (granulocyte colony-stimulating factor and IL-8) hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is completely inhibited after low-dose (0.5 Gy) total-body irradiation (TBI). Because neutrophil granular proteases are regulatory mediators in cytokineinduced HSC͞HPC mobilization, we considered a possible role for protease inhibitors in the induction of HSC͞HPC mobilization. Bone marrow (BM) extracellular extracts that were obtained from murine femurs after 0.5 Gy of TBI contained an inhibitor of elastase. Also, after low-dose TBI, both Serpina1 mRNA and protein concentrations were increased in BM extracts, compared with extracts that were obtained from controls. The inhibitory activity in BM extracts of irradiated mice was reversed by addition of an Ab directed against Serpina1. To further study a possible in vivo role of Serpina1 in HSC͞HPC mobilization, we administered Serpina1 before IL-8 injection. This administration resulted in an almost complete inhibition of HSC͞HPC mobilization, whereas heat-inactivated Serpina1 had no effect. These results indicate that low-dose TBI inhibits cytokine-induced HSC͞HPC mobilization and induces Serpina1 in the BM. Because exogenous administration of Serpina1 inhibits mobilization, we propose that radiation-induced Serpina1 is responsible for the inhibition of HSC͞HPC mobilization. Also, we hypothesize that cytokine-induced HSC͞HPC mobilization is determined by a critical balance between serine proteases and serine protease inhibitors.protease ͉ protease inhibitors ͉ bone marrow ͉ adhesion molecules

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The structural puzzle of how serpin serine proteinase inhibitors work

Cited by 64 publications

References 71 publications

Serpin 2a Is Induced in Activated Macrophages and Conjugates to a Ubiquitin Homolog

Serpin 2a Is Induced in Activated Macrophages and Conjugates to a Ubiquitin Homolog

Alzheimer's Peptide Aβ1–42 Binds to Two β-Sheets of α1-Antichymotrypsin and Transforms It from Inhibitor to Substrate

Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization

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