The role of beta-strand 5A of plasminogen activator inhibitor-1 in regulation of its latency transition and inhibitory activity by vitronectin

Signe Jensen, Tove Kirkegaard, Katrine E Pedersen, Marta Busse, Klaus T Preissner, Kees W Rodenburg, Peter A Andreasen

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    Abstrakt

    Plasminogen activator inhibitor-1 (PAI-1) is a potential target for anti-thrombotic and anti-cancer therapy. It circulates in plasma in a complex with vitronectin (VN). We have studied biochemical mechanisms for PAI-1 neutralisation and its modulation by VN, using site-directed mutagenesis and limited proteolysis. We demonstrate that VN, besides delaying conversion of PAI-1 to the inactive latent form, also protects PAI-1 against cold- and detergent-induced substrate behaviour and counteracts conversion of PAI-1 to inert forms by certain amphipathic organochemical compounds. VN protection against cold- and detergent-induced substrate behaviour is associated with inhibition of the proteolytic susceptibility of beta-strand 5A. Alanine substitution of a lysine residue placed centrally in beta-strand 5A implied a VN-induced acceleration of latency transition, instead of the normal delay. This substitution not only protects PAI-1 against neutralisation, but also counteracts VN-induced protection against neutralisation. We conclude that beta-strand 5A plays a crucial role in VN-regulation of PAI-1 activity.

    OriginalsprogEngelsk
    Sider (fra-til)301-10
    Antal sider10
    TidsskriftBiochimica et Biophysica Acta - General Subjects
    Vol/bind1597
    Udgave nummer2
    DOI
    StatusUdgivet - 3 jun. 2002

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