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Activation of the zymogen to urokinase-type plasminogen activator is associated with increased interdomain flexibility

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Activation of the zymogen to urokinase-type plasminogen activator is associated with increased interdomain flexibility. / Behrens, Manja A; Bøtkjær, Kenneth Alrø; Goswami, Sumit; Oliveira, Cristiano L P; Jensen, Jan K; Schar, Christine R; Declerck, Paul J; Peterson, Cynthia B; Andreasen, Peter A; Pedersen, Jan Skov.

I: Journal of Molecular Biology, Bind 411, Nr. 2, 12.08.2011, s. 417-29.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Harvard

Behrens, MA, Bøtkjær, KA, Goswami, S, Oliveira, CLP, Jensen, JK, Schar, CR, Declerck, PJ, Peterson, CB, Andreasen, PA & Pedersen, JS 2011, 'Activation of the zymogen to urokinase-type plasminogen activator is associated with increased interdomain flexibility', Journal of Molecular Biology, bind 411, nr. 2, s. 417-29. https://doi.org/10.1016/j.jmb.2011.05.026

APA

CBE

Behrens MA, Bøtkjær KA, Goswami S, Oliveira CLP, Jensen JK, Schar CR, Declerck PJ, Peterson CB, Andreasen PA, Pedersen JS. 2011. Activation of the zymogen to urokinase-type plasminogen activator is associated with increased interdomain flexibility. Journal of Molecular Biology. 411(2):417-29. https://doi.org/10.1016/j.jmb.2011.05.026

MLA

Vancouver

Author

Behrens, Manja A ; Bøtkjær, Kenneth Alrø ; Goswami, Sumit ; Oliveira, Cristiano L P ; Jensen, Jan K ; Schar, Christine R ; Declerck, Paul J ; Peterson, Cynthia B ; Andreasen, Peter A ; Pedersen, Jan Skov. / Activation of the zymogen to urokinase-type plasminogen activator is associated with increased interdomain flexibility. I: Journal of Molecular Biology. 2011 ; Bind 411, Nr. 2. s. 417-29.

Bibtex

@article{6f7c2aa09de445febab80ba4a4c79bc6,
title = "Activation of the zymogen to urokinase-type plasminogen activator is associated with increased interdomain flexibility",
abstract = "A key regulatory step for serine proteases of the trypsin clan is activation of the initially secreted zymogens, leading to an increase in activity by orders of magnitude. Zymogen activation occurs by cleavage of a single peptide bond near the N-terminus of the catalytic domain. Besides the catalytic domain, most serine proteases have N-terminal A-chains with independently folded domains. Little is known about how zymogen activation affects the interplay between domains. This question is investigated with urokinase-type plasminogen activator (uPA), which has an epidermal growth factor domain and a kringle domain, connected to the catalytic domain by a 15-residue linker. uPA has been implicated under several pathological conditions, and one possibility for pharmacological control is targeting the conversion of the zymogen pro-uPA to active uPA. Therefore, a small-angle X-ray scattering study of the conformations of pro-uPA and uPA in solution was performed. Structural models for the proteins were derived using available atomic-resolution structures for the various domains. Active uPA was found to be flexible with a random conformation of the amino-terminal fragment domain with respect to the serine protease domain. In contrast, pro-uPA was observed to be rigid, with the amino-terminal fragment domain in a fixed position with respect to the serine protease domain. Analytical ultracentrifugation analysis supported the observed difference between pro-uPA and uPA in overall shape and size seen with small-angle X-ray scattering. Upon association of either of two monoclonal Fab (fragment antigen-binding) fragments that are directed against the catalytic domain of, respectively, pro-uPA and uPA, rigid structures were formed.",
keywords = "Enzyme Precursors, Humans, Models, Molecular, Protein Conformation, Protein Structure, Tertiary, Scattering, Small Angle, Serine Proteases, Ultracentrifugation, Urokinase-Type Plasminogen Activator",
author = "Behrens, {Manja A} and B{\o}tkj{\ae}r, {Kenneth Alr{\o}} and Sumit Goswami and Oliveira, {Cristiano L P} and Jensen, {Jan K} and Schar, {Christine R} and Declerck, {Paul J} and Peterson, {Cynthia B} and Andreasen, {Peter A} and Pedersen, {Jan Skov}",
note = "Copyright {\circledC} 2011 Elsevier Ltd. All rights reserved.",
year = "2011",
month = "8",
day = "12",
doi = "10.1016/j.jmb.2011.05.026",
language = "English",
volume = "411",
pages = "417--29",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
publisher = "Academic Press",
number = "2",

}

RIS

TY - JOUR

T1 - Activation of the zymogen to urokinase-type plasminogen activator is associated with increased interdomain flexibility

AU - Behrens, Manja A

AU - Bøtkjær, Kenneth Alrø

AU - Goswami, Sumit

AU - Oliveira, Cristiano L P

AU - Jensen, Jan K

AU - Schar, Christine R

AU - Declerck, Paul J

AU - Peterson, Cynthia B

AU - Andreasen, Peter A

AU - Pedersen, Jan Skov

N1 - Copyright © 2011 Elsevier Ltd. All rights reserved.

PY - 2011/8/12

Y1 - 2011/8/12

N2 - A key regulatory step for serine proteases of the trypsin clan is activation of the initially secreted zymogens, leading to an increase in activity by orders of magnitude. Zymogen activation occurs by cleavage of a single peptide bond near the N-terminus of the catalytic domain. Besides the catalytic domain, most serine proteases have N-terminal A-chains with independently folded domains. Little is known about how zymogen activation affects the interplay between domains. This question is investigated with urokinase-type plasminogen activator (uPA), which has an epidermal growth factor domain and a kringle domain, connected to the catalytic domain by a 15-residue linker. uPA has been implicated under several pathological conditions, and one possibility for pharmacological control is targeting the conversion of the zymogen pro-uPA to active uPA. Therefore, a small-angle X-ray scattering study of the conformations of pro-uPA and uPA in solution was performed. Structural models for the proteins were derived using available atomic-resolution structures for the various domains. Active uPA was found to be flexible with a random conformation of the amino-terminal fragment domain with respect to the serine protease domain. In contrast, pro-uPA was observed to be rigid, with the amino-terminal fragment domain in a fixed position with respect to the serine protease domain. Analytical ultracentrifugation analysis supported the observed difference between pro-uPA and uPA in overall shape and size seen with small-angle X-ray scattering. Upon association of either of two monoclonal Fab (fragment antigen-binding) fragments that are directed against the catalytic domain of, respectively, pro-uPA and uPA, rigid structures were formed.

AB - A key regulatory step for serine proteases of the trypsin clan is activation of the initially secreted zymogens, leading to an increase in activity by orders of magnitude. Zymogen activation occurs by cleavage of a single peptide bond near the N-terminus of the catalytic domain. Besides the catalytic domain, most serine proteases have N-terminal A-chains with independently folded domains. Little is known about how zymogen activation affects the interplay between domains. This question is investigated with urokinase-type plasminogen activator (uPA), which has an epidermal growth factor domain and a kringle domain, connected to the catalytic domain by a 15-residue linker. uPA has been implicated under several pathological conditions, and one possibility for pharmacological control is targeting the conversion of the zymogen pro-uPA to active uPA. Therefore, a small-angle X-ray scattering study of the conformations of pro-uPA and uPA in solution was performed. Structural models for the proteins were derived using available atomic-resolution structures for the various domains. Active uPA was found to be flexible with a random conformation of the amino-terminal fragment domain with respect to the serine protease domain. In contrast, pro-uPA was observed to be rigid, with the amino-terminal fragment domain in a fixed position with respect to the serine protease domain. Analytical ultracentrifugation analysis supported the observed difference between pro-uPA and uPA in overall shape and size seen with small-angle X-ray scattering. Upon association of either of two monoclonal Fab (fragment antigen-binding) fragments that are directed against the catalytic domain of, respectively, pro-uPA and uPA, rigid structures were formed.

KW - Enzyme Precursors

KW - Humans

KW - Models, Molecular

KW - Protein Conformation

KW - Protein Structure, Tertiary

KW - Scattering, Small Angle

KW - Serine Proteases

KW - Ultracentrifugation

KW - Urokinase-Type Plasminogen Activator

U2 - 10.1016/j.jmb.2011.05.026

DO - 10.1016/j.jmb.2011.05.026

M3 - Journal article

C2 - 21669207

VL - 411

SP - 417

EP - 429

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

IS - 2

ER -