Latency transition of plasminogen activator inhibitor type 1 is evolutionarily conserved.

Agnieszka Jendroszek; Malene Sønnichsen; Andres Chana Munoz; Kato Leyman; Anni Christensen; Steen Vang Petersen; Christian Bendixen; Frank Panitz; Peter Andreasen; Jan Kristian Jensen

doi:10.1160/TH17-02-0102

Latency transition of plasminogen activator inhibitor type 1 is evolutionarily conserved.

Agnieszka Jendroszek, Malene Sønnichsen, Andres Chana Munoz, Kato Leyman, Anni Christensen, Steen Vang Petersen, Christian Bendixen, Frank Panitz, Peter Andreasen, Jan Kristian Jensen

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

6 Citationer (Scopus)

Abstract

Plasminogen activator inhibitor type 1 (PAI-1) is a central regulator of fibrinolysis and tissue remodelling. PAI-1 belongs to the serpin superfamily and unlike other inhibitory serpins undergoes a spontaneous inactivation process under physiological conditions, termed latency transition. During latency transition the solvent exposed reactive centre loop is inserted into the central _–sheet A of the molecule, and is no longer accessible to reaction with the protease. More than three decades of research on mammalian PAI-1 has not been able to clarify the evolutionary advantage and physiological relevance of latency transition. In order to study the origin of PAI-1 latency transition, we produced PAI-1 from Spiny dogfish shark (Squalus acanthias) and African lungfish (Protopterus sp.), which represent central species in the evolution of vertebrates. Although human PAI-1 and the non-mammalian PAI-1 variants share only approximately 50 % sequence identity, our results showed that all tested PAI–1 variants undergo latency transition with a similar rate. Since the functional stability of PAI–1 can be greatly increased by substitution of few amino acid residues, we conclude that the ability to undergo latency transition must have been a specific selection criterion for the evolution of PAI-1. It appears that all PAI-1 molecules must harbour latency transition to fulfil their physiological function, stressing the importance to further pursue a complete understanding of this molecular phenomenon with possible implication to pharmacological intervention. Our results provide the next step in understanding how the complete role of this important protease inhibitor evolved along with the fibrinolytic system.

Originalsprog	Engelsk
Tidsskrift	Thrombosis and Haemostasis
Vol/bind	117
Nummer	9
Sider (fra-til)	1688-1699
Antal sider	12
ISSN	0340-6245
DOI	https://doi.org/10.1160/TH17-02-0102
Status	Udgivet - 30 aug. 2017

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title = "Latency transition of plasminogen activator inhibitor type 1 is evolutionarily conserved.",

abstract = "Plasminogen activator inhibitor type 1 (PAI-1) is a central regulator of fibrinolysis and tissue remodelling. PAI-1 belongs to the serpin superfamily and unlike other inhibitory serpins undergoes a spontaneous inactivation process under physiological conditions, termed latency transition. During latency transition the solvent exposed reactive centre loop is inserted into the central _–sheet A of the molecule, and is no longer accessible to reaction with the protease. More than three decades of research on mammalian PAI-1 has not been able to clarify the evolutionary advantage and physiological relevance of latency transition. In order to study the origin of PAI-1 latency transition, we produced PAI-1 from Spiny dogfish shark (Squalus acanthias) and African lungfish (Protopterus sp.), which represent central species in the evolution of vertebrates. Although human PAI-1 and the non-mammalian PAI-1 variants share only approximately 50 % sequence identity, our results showed that all tested PAI–1 variants undergo latency transition with a similar rate. Since the functional stability of PAI–1 can be greatly increased by substitution of few amino acid residues, we conclude that the ability to undergo latency transition must have been a specific selection criterion for the evolution of PAI-1. It appears that all PAI-1 molecules must harbour latency transition to fulfil their physiological function, stressing the importance to further pursue a complete understanding of this molecular phenomenon with possible implication to pharmacological intervention. Our results provide the next step in understanding how the complete role of this important protease inhibitor evolved along with the fibrinolytic system.",

keywords = "Conformational change, Homology, Thermodynamic stability, Tissue type plasminogen activator, Urokinase",

author = "Agnieszka Jendroszek and Malene S{\o}nnichsen and {Chana Munoz}, Andres and Kato Leyman and Anni Christensen and Petersen, {Steen Vang} and Christian Bendixen and Frank Panitz and Peter Andreasen and Jensen, {Jan Kristian}",

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T1 - Latency transition of plasminogen activator inhibitor type 1 is evolutionarily conserved.

AU - Jendroszek, Agnieszka

AU - Sønnichsen, Malene

AU - Chana Munoz, Andres

AU - Leyman, Kato

AU - Christensen, Anni

AU - Petersen, Steen Vang

AU - Bendixen, Christian

AU - Panitz, Frank

AU - Andreasen, Peter

AU - Jensen, Jan Kristian

PY - 2017/8/30

Y1 - 2017/8/30

N2 - Plasminogen activator inhibitor type 1 (PAI-1) is a central regulator of fibrinolysis and tissue remodelling. PAI-1 belongs to the serpin superfamily and unlike other inhibitory serpins undergoes a spontaneous inactivation process under physiological conditions, termed latency transition. During latency transition the solvent exposed reactive centre loop is inserted into the central _–sheet A of the molecule, and is no longer accessible to reaction with the protease. More than three decades of research on mammalian PAI-1 has not been able to clarify the evolutionary advantage and physiological relevance of latency transition. In order to study the origin of PAI-1 latency transition, we produced PAI-1 from Spiny dogfish shark (Squalus acanthias) and African lungfish (Protopterus sp.), which represent central species in the evolution of vertebrates. Although human PAI-1 and the non-mammalian PAI-1 variants share only approximately 50 % sequence identity, our results showed that all tested PAI–1 variants undergo latency transition with a similar rate. Since the functional stability of PAI–1 can be greatly increased by substitution of few amino acid residues, we conclude that the ability to undergo latency transition must have been a specific selection criterion for the evolution of PAI-1. It appears that all PAI-1 molecules must harbour latency transition to fulfil their physiological function, stressing the importance to further pursue a complete understanding of this molecular phenomenon with possible implication to pharmacological intervention. Our results provide the next step in understanding how the complete role of this important protease inhibitor evolved along with the fibrinolytic system.

AB - Plasminogen activator inhibitor type 1 (PAI-1) is a central regulator of fibrinolysis and tissue remodelling. PAI-1 belongs to the serpin superfamily and unlike other inhibitory serpins undergoes a spontaneous inactivation process under physiological conditions, termed latency transition. During latency transition the solvent exposed reactive centre loop is inserted into the central _–sheet A of the molecule, and is no longer accessible to reaction with the protease. More than three decades of research on mammalian PAI-1 has not been able to clarify the evolutionary advantage and physiological relevance of latency transition. In order to study the origin of PAI-1 latency transition, we produced PAI-1 from Spiny dogfish shark (Squalus acanthias) and African lungfish (Protopterus sp.), which represent central species in the evolution of vertebrates. Although human PAI-1 and the non-mammalian PAI-1 variants share only approximately 50 % sequence identity, our results showed that all tested PAI–1 variants undergo latency transition with a similar rate. Since the functional stability of PAI–1 can be greatly increased by substitution of few amino acid residues, we conclude that the ability to undergo latency transition must have been a specific selection criterion for the evolution of PAI-1. It appears that all PAI-1 molecules must harbour latency transition to fulfil their physiological function, stressing the importance to further pursue a complete understanding of this molecular phenomenon with possible implication to pharmacological intervention. Our results provide the next step in understanding how the complete role of this important protease inhibitor evolved along with the fibrinolytic system.

KW - Conformational change

KW - Homology

KW - Thermodynamic stability

KW - Tissue type plasminogen activator

KW - Urokinase

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U2 - 10.1160/TH17-02-0102

DO - 10.1160/TH17-02-0102

M3 - Journal article

C2 - 28771275

SN - 0340-6245

VL - 117

SP - 1688

EP - 1699

JO - Thrombosis and Haemostasis

JF - Thrombosis and Haemostasis

IS - 9

ER -

Latency transition of plasminogen activator inhibitor type 1 is evolutionarily conserved.

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