The role of β-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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引用次数: 8

Abstract

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 β-strand 5A. Alanine substitution of a lysine residue placed centrally in β-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 β-strand 5A plays a crucial role in VN-regulation of PAI-1 activity.

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纤溶酶原激活物抑制剂-1 β-链5A在调节其潜伏期转变和玻璃体连接蛋白抑制活性中的作用
纤溶酶原激活物抑制剂-1 (PAI-1)是抗血栓和抗癌治疗的潜在靶点。它与玻璃体粘连蛋白(VN)在血浆中循环。我们利用定点诱变和有限蛋白水解研究了PAI-1中和及其由VN调节的生化机制。我们证明,VN除了延迟PAI-1转化为无活性潜伏形式外,还保护PAI-1免受冷和洗涤剂诱导的底物行为,并抵消某些两亲性有机化合物将PAI-1转化为惰性形式。VN对低温和洗涤剂诱导的底物行为的保护作用与抑制β-链5A的蛋白水解敏感性有关。位于β-链5A中心的赖氨酸残基的丙氨酸取代意味着vn诱导的潜伏期转变加速,而不是正常的延迟。这种取代不仅可以保护PAI-1免受中和,还可以抵消vn诱导的对中和的保护。我们得出结论,β-链5A在vn调节PAI-1活性中起着至关重要的作用。
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