Signe Jensen , Tove Kirkegaard , Katrine E. Pedersen , Marta Busse , Klaus T. Preissner , Kees W. Rodenburg , Peter A. Andreasen
{"title":"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","authors":"Signe Jensen , Tove Kirkegaard , Katrine E. Pedersen , Marta Busse , Klaus T. Preissner , Kees W. Rodenburg , Peter A. Andreasen","doi":"10.1016/S0167-4838(02)00312-6","DOIUrl":null,"url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":100166,"journal":{"name":"Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology","volume":"1597 2","pages":"Pages 301-310"},"PeriodicalIF":0.0000,"publicationDate":"2002-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0167-4838(02)00312-6","citationCount":"8","resultStr":"{\"title\":\"The role of β-strand 5A of plasminogen activator inhibitor-1 in regulation of its latency transition and inhibitory activity by vitronectin\",\"authors\":\"Signe Jensen , Tove Kirkegaard , Katrine E. Pedersen , Marta Busse , Klaus T. Preissner , Kees W. Rodenburg , Peter A. Andreasen\",\"doi\":\"10.1016/S0167-4838(02)00312-6\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>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.</p></div>\",\"PeriodicalId\":100166,\"journal\":{\"name\":\"Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology\",\"volume\":\"1597 2\",\"pages\":\"Pages 301-310\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2002-06-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1016/S0167-4838(02)00312-6\",\"citationCount\":\"8\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0167483802003126\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0167483802003126","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
The role of β-strand 5A of plasminogen activator inhibitor-1 in regulation of its latency transition and inhibitory activity by vitronectin
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.