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The axonally secreted serine proteinase inhibitor, neuroserpin, inhibits plasminogen activators and plasmin but not thrombin.


Osterwalder, T; Cinelli, P; Baici, A; Pennella, A; Krueger, S R; Schrimpf, S P; Meins, M; Sonderegger, P (1998). The axonally secreted serine proteinase inhibitor, neuroserpin, inhibits plasminogen activators and plasmin but not thrombin. Journal of Biological Chemistry, 273(4):2312-2321.

Abstract

Neuroserpin is an axonally secreted serine proteinase inhibitor that is expressed in neurons during embryogenesis and in the adult nervous system. To identify target proteinases, we used a eucaryotic expression system based on the mouse myeloma cell line J558L and vectors including a promoter from an Ig-kappa-variable region, an Ig-kappa enhancer, and the exon encoding the Ig-kappa constant region (C kappa) and produced recombinant neuroserpin as a wild-type protein or as a fusion protein with C kappa. We investigated the capability of recombinant neuroserpin to form SDS-stable complexes with, and to reduce the amidolytic activity of, a variety of serine proteinases in vitro. Consistent with its primary structure at the reactive site, neuroserpin exhibited inhibitory activity against trypsin-like proteinases. Although neuroserpin bound and inactivated plasminogen activators and plasmin, no interaction was observed with thrombin. A reactive site mutant of neuroserpin neither formed complexes with nor inhibited the amidolytic activity of any of the tested proteinases. Kinetic analysis of the inhibitory activity revealed neuroserpin to be a slow binding inhibitor of plasminogen activators and plasmin. Thus, we postulate that neuroserpin could represent a regulatory element of extracellular proteolytic events in the nervous system mediated by plasminogen activators or plasmin.

Neuroserpin is an axonally secreted serine proteinase inhibitor that is expressed in neurons during embryogenesis and in the adult nervous system. To identify target proteinases, we used a eucaryotic expression system based on the mouse myeloma cell line J558L and vectors including a promoter from an Ig-kappa-variable region, an Ig-kappa enhancer, and the exon encoding the Ig-kappa constant region (C kappa) and produced recombinant neuroserpin as a wild-type protein or as a fusion protein with C kappa. We investigated the capability of recombinant neuroserpin to form SDS-stable complexes with, and to reduce the amidolytic activity of, a variety of serine proteinases in vitro. Consistent with its primary structure at the reactive site, neuroserpin exhibited inhibitory activity against trypsin-like proteinases. Although neuroserpin bound and inactivated plasminogen activators and plasmin, no interaction was observed with thrombin. A reactive site mutant of neuroserpin neither formed complexes with nor inhibited the amidolytic activity of any of the tested proteinases. Kinetic analysis of the inhibitory activity revealed neuroserpin to be a slow binding inhibitor of plasminogen activators and plasmin. Thus, we postulate that neuroserpin could represent a regulatory element of extracellular proteolytic events in the nervous system mediated by plasminogen activators or plasmin.

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Additional indexing

Item Type:Journal Article, refereed
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:23 January 1998
Deposited On:11 Feb 2008 12:20
Last Modified:26 Aug 2016 07:32
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
Funders:Olga Mayenfisch Stiftung, Helmut Horten Stiftung, Ciba-Geigy-Jubiläumsstiftung, Hartmann Müller-Stiftung, EMDO-Stiftung, Wolfermann-Nägeli-Stiftung, Union Bank of Switzerland on behalf of a client.
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1074/jbc.273.4.2312
Related URLs:http://www.jbc.org/cgi/content/full/273/4/2312
PubMed ID:9442076
Permanent URL: http://doi.org/10.5167/uzh-1071

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