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Guido Epple, Kristina Langfeld, Michael Baier, Hermann-Georg Holzhtter, Wolf-Dieter Schleuning, Eckart Kttgen, Reinhard Gener, Michael Praus
Both lysine-clusters of the NH2-terminal prion-protein fragment PrP23-110 are essential for t-PA mediated plasminogen activation
We have recently shown that the NH2-terminal fragment (PrP23-110) of the human cellular prion protein (PrPc ) stimulates t-PA mediated plasminogen activation. PrP23-110 contains an N-terminal lysine cluster (LC1; K23 ,K24, K27) and a C-terminal one (LC2; K101,K104,K106,K110). To study their biological function we have substituted all lysine residues of each cluster by alanine and generated the recombinant PrP proteins PrP23-110sLC1 and PrP23-110sLC2. The ability of the mutant proteins to stimulate plasminogen activation was assayed. We found that both lysine clusters are essential for t-PA mediated plasminogen activation. We further studied the binding of soluble PrP23-110 to immobilized t-PA or plasminogen using surface plasmon resonance. The recorded binding curves could not be modeled by classical 1:1 binding kinetics suggesting oligomerisation of PrP23-110. Further plasmon resonance studies show that indeed PrP23-110 binds to itself and that glycosaminoglycans modify this interaction. Binding of t-PA or plasminogen to PrP23-110 was no longer influenced by glycosaminoglycans when PrP23-110 was immobilized on the chip surface. Thus a possible role of heparin as a cofactor in the stimulation of plasminogen activation by t-PA could be the generation of a PrP23-110 form with both lysine clusters accessible for binding of t-PA and plasminogen.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 91, 03/2004
Pages: 465 - 472