Crystal structure of plasminogen activator inhibitor-1 in an active conformation with normal thermodynamic stability

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Crystal structure of plasminogen activator inhibitor-1 in an active conformation with normal thermodynamic stability. / Jensen, Jan K; Thompson, Lawrence C; Bucci, Joel C; Nissen, Poul; Gettins, Peter G W; Peterson, Cynthia B; Andreasen, Peter A; Morth, J Preben.

In: Journal of Biological Chemistry, Vol. 286, No. 34, 2011, p. 29709-17.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Jensen, JK, Thompson, LC, Bucci, JC, Nissen, P, Gettins, PGW, Peterson, CB, Andreasen, PA & Morth, JP 2011, 'Crystal structure of plasminogen activator inhibitor-1 in an active conformation with normal thermodynamic stability', Journal of Biological Chemistry, vol. 286, no. 34, pp. 29709-17. https://doi.org/10.1074/jbc.M111.236554

APA

Jensen, J. K., Thompson, L. C., Bucci, J. C., Nissen, P., Gettins, P. G. W., Peterson, C. B., ... Morth, J. P. (2011). Crystal structure of plasminogen activator inhibitor-1 in an active conformation with normal thermodynamic stability. Journal of Biological Chemistry, 286(34), 29709-17. https://doi.org/10.1074/jbc.M111.236554

CBE

Jensen JK, Thompson LC, Bucci JC, Nissen P, Gettins PGW, Peterson CB, Andreasen PA, Morth JP. 2011. Crystal structure of plasminogen activator inhibitor-1 in an active conformation with normal thermodynamic stability. Journal of Biological Chemistry. 286(34):29709-17. https://doi.org/10.1074/jbc.M111.236554

MLA

Vancouver

Author

Jensen, Jan K ; Thompson, Lawrence C ; Bucci, Joel C ; Nissen, Poul ; Gettins, Peter G W ; Peterson, Cynthia B ; Andreasen, Peter A ; Morth, J Preben. / Crystal structure of plasminogen activator inhibitor-1 in an active conformation with normal thermodynamic stability. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 34. pp. 29709-17.

Bibtex

@article{6a461e91c9c948b0804310f5d9fcc522,
title = "Crystal structure of plasminogen activator inhibitor-1 in an active conformation with normal thermodynamic stability",
abstract = "The serpin plasminogen activator inhibitor-1 (PAI-1) is a crucial regulator in fibrinolysis and tissue remodeling. PAI-1 has been associated with several pathological conditions and is a validated prognostic marker in human cancers. However, structural information about the native inhibitory form of PAI-1 has been elusive because of its inherent conformational instability and rapid conversion to a latent, inactive structure. Here we report the crystal structure of PAI-1 W175F at 2.3 Å resolution as the first model of the metastable native molecule. Structural comparison with a quadruple mutant (14-1B) previously used as representative of the active state uncovered key differences. The most striking differences occur near the region that houses three of the four mutations in the 14-1B PAI-1 structure. Prominent changes are localized within a loop connecting β-strand 3A with the F helix, in which a previously observed 3(10)-helix is absent in the new structure. Notably these structural changes are found near the binding site for the cofactor vitronectin. Because vitronectin is the only known physiological regulator of PAI-1 that slows down the latency conversion, the structure of this region is important. Furthermore, the previously identified chloride-binding site close to the F-helix is absent from the present structure and likely to be artifactual, because of its dependence on the 14-1B mutations. Instead we found a different chlorine-binding site that is likely to be present in wild type PAI-1 and that more satisfactorily accounts for the chlorine stabilizing effect on PAI-1.",
keywords = "Crystallography, X-Ray, Humans, Mutation, Missense, Plasminogen Activator Inhibitor 1, Protein Stability, Protein Structure, Secondary, Thermodynamics",
author = "Jensen, {Jan K} and Thompson, {Lawrence C} and Bucci, {Joel C} and Poul Nissen and Gettins, {Peter G W} and Peterson, {Cynthia B} and Andreasen, {Peter A} and Morth, {J Preben}",
year = "2011",
doi = "10.1074/jbc.M111.236554",
language = "English",
volume = "286",
pages = "29709--17",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",
number = "34",

}

RIS

TY - JOUR

T1 - Crystal structure of plasminogen activator inhibitor-1 in an active conformation with normal thermodynamic stability

AU - Jensen, Jan K

AU - Thompson, Lawrence C

AU - Bucci, Joel C

AU - Nissen, Poul

AU - Gettins, Peter G W

AU - Peterson, Cynthia B

AU - Andreasen, Peter A

AU - Morth, J Preben

PY - 2011

Y1 - 2011

N2 - The serpin plasminogen activator inhibitor-1 (PAI-1) is a crucial regulator in fibrinolysis and tissue remodeling. PAI-1 has been associated with several pathological conditions and is a validated prognostic marker in human cancers. However, structural information about the native inhibitory form of PAI-1 has been elusive because of its inherent conformational instability and rapid conversion to a latent, inactive structure. Here we report the crystal structure of PAI-1 W175F at 2.3 Å resolution as the first model of the metastable native molecule. Structural comparison with a quadruple mutant (14-1B) previously used as representative of the active state uncovered key differences. The most striking differences occur near the region that houses three of the four mutations in the 14-1B PAI-1 structure. Prominent changes are localized within a loop connecting β-strand 3A with the F helix, in which a previously observed 3(10)-helix is absent in the new structure. Notably these structural changes are found near the binding site for the cofactor vitronectin. Because vitronectin is the only known physiological regulator of PAI-1 that slows down the latency conversion, the structure of this region is important. Furthermore, the previously identified chloride-binding site close to the F-helix is absent from the present structure and likely to be artifactual, because of its dependence on the 14-1B mutations. Instead we found a different chlorine-binding site that is likely to be present in wild type PAI-1 and that more satisfactorily accounts for the chlorine stabilizing effect on PAI-1.

AB - The serpin plasminogen activator inhibitor-1 (PAI-1) is a crucial regulator in fibrinolysis and tissue remodeling. PAI-1 has been associated with several pathological conditions and is a validated prognostic marker in human cancers. However, structural information about the native inhibitory form of PAI-1 has been elusive because of its inherent conformational instability and rapid conversion to a latent, inactive structure. Here we report the crystal structure of PAI-1 W175F at 2.3 Å resolution as the first model of the metastable native molecule. Structural comparison with a quadruple mutant (14-1B) previously used as representative of the active state uncovered key differences. The most striking differences occur near the region that houses three of the four mutations in the 14-1B PAI-1 structure. Prominent changes are localized within a loop connecting β-strand 3A with the F helix, in which a previously observed 3(10)-helix is absent in the new structure. Notably these structural changes are found near the binding site for the cofactor vitronectin. Because vitronectin is the only known physiological regulator of PAI-1 that slows down the latency conversion, the structure of this region is important. Furthermore, the previously identified chloride-binding site close to the F-helix is absent from the present structure and likely to be artifactual, because of its dependence on the 14-1B mutations. Instead we found a different chlorine-binding site that is likely to be present in wild type PAI-1 and that more satisfactorily accounts for the chlorine stabilizing effect on PAI-1.

KW - Crystallography, X-Ray

KW - Humans

KW - Mutation, Missense

KW - Plasminogen Activator Inhibitor 1

KW - Protein Stability

KW - Protein Structure, Secondary

KW - Thermodynamics

U2 - 10.1074/jbc.M111.236554

DO - 10.1074/jbc.M111.236554

M3 - Journal article

C2 - 21697084

VL - 286

SP - 29709

EP - 29717

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 34

ER -