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          Institute: MPI für Infektionsbiologie     Collection: Core Facilites     Display Documents

ID: 126524.0, MPI für Infektionsbiologie / Core Facilites
Stimulation of plasminogen activation by recombinant cellular prion protein is conserved in the NH2-terminal fragment PrP23-110
Authors:Praus, Michael; Kettelgerdes, Gerhard; Baier, Michael; Holzhütter, Hermann-Georg; Jungblut, Peter R.; Maissen, Manuela; Epple, Guido; Schleuning, Wolf-Dieter; Kottgen, Eckart; Aguzzi, Adriano; Gessner, Reinhard
Date of Publication (YYYY-MM-DD):2003-05
Title of Journal:Thrombosis and Haemostasis
Journal Abbrev.:Thromb. Haemost.
Issue / Number:5
Start Page:812
End Page:819
Review Status:not specified
Audience:Experts Only
Abstract / Description:The cellular prion protein (PrPc), tissue-type plasminogen activator (t-PA) and plasminogen are expressed in synaptic membranes in vivo. In the central nervous system the fibrinolytic system is associated with excitotoxin-mediated neurotoxicity and Alzheimer's disease. Recently binding of the disease associated isoform of the prion protein (PrPSc) to plasminogen and stimulation of t-PA activity have been reported. In this study the interaction of PrPc and plasminogen was investigated using chromogenic assays in vitro.We found that plasmin is able to cleave recombinant PrPc at lysine residue 110 generating an NH2-terminal truncated molecule that has previously been described as a major product of PrPc metabolism.We further characterized the proteolytic fragments with respect to their ability to stimulate plasminogen activation in vitro. Our results show that the NH2-terminal part of PrPc spanning amino acids 23-110 (PrP23-110) together with low molecular weight heparin stimulates t-PA mediated plasminogen activation in vitro. The apparent rate constant was increased 57 fold in the presence of 800 nM PrP23-110. Furthermore,we compared the stimulation of t-PA activity by PrPc and beta-amyloid peptide (1-42).While the activity of the beta-amyloid was independent of low molecular weight heparin, PrP23-110 was approximately 4- and 37 fold more active than beta-amyloid in the absence or presence of low molecular weight heparin. In summary, plasmin cleaves PrPc in vitro and the liberated NH2-terminal fragment accelerates plasminogen activation. Cleavage of PrPc has previously been reported.Thus cleavage of PrPcenhancing plasminogen activation at the cell surface could constitute a regulatory mechanism of pericellular proteolysis.
Free Keywords:Cellular prion protein (PrPc), tissue-type plasminogen activator (t-PA), plasminogen, central nervous system
External Publication Status:published
Document Type:Article
Communicated by:Hilmar Fünning
Affiliations:MPI für Infektionsbiologie/Core Facilities
External Affiliations:Humboldt Univ, Fak Med, Inst Lab Med & Pathobiochem, Charite Berlin, D-13353 Berlin, Germany.; Robert Koch Inst, D-1000 Berlin, Germany.; Humboldt Univ, Fak Med, Inst Biochem, Charite, D-13353 Berlin, Germany.; Univ Spital Zurich, Inst Neuropathol, Zurich, Switzerland.; Schering Res Labs, Berlin, Germany.
Identifiers:ISI:000184624100007 [ID No:1]
ISSN:0340-6245 [ID No:2]
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