Importance of intramolecular interactions in the control of the fibrin affinity and activation of human plasminogen

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Abstract

Incubation of human Glu-plasminogen with 1,5-difluoro-2,4-dinitrobenzene leads to the specific intramolecular cross-linking of the kringle 1+2+3 region and the light (B) chain region of plasminogen. This cross-link was found to prevent the conformational change which is induced in Glu-plasminogen by lysine analogues or by proteolytic removal of the N2-terminal peptide. Our results suggest that the cross-link freezes the closed conformation of Glu-plasminogen, and it seems likely that the transition to the loose conformer requires separation of the kringle 1+2+3 region from the light (B) chain portion. The change in the relative position of these regions during the conformational change in plasminogen is also indicated by our observation that the rate of formation of the intramolecular cross-link is significantly decreased when transition to the loose conformer is induced either by saturation or the lysine-binding sites or by conversion to Lys-plasminogen. Cross-linked Glu-plasminogen is slowly activated by urokinase and melanoma tissue plasminogen activator, but in contrast with uncross-linked Glu-plasminogen conversion to Lys-plasminogen or saturation of lysine-binding sites with ligand does not increase the rate of activation because the cross-link prevents transition to the loose conformer wich is susceptible to activation. The fibrin affinity of cross-linked Glu-plasminogen is practically identical with that of Glu-plasminogen. As in the case of uncross-linked Glu-plasminogen, removal of the NH2-terminal peptide causes a marked increase in fibrin affinity although the resulting cross-linked Lys-plasminogen is fixed in the closed conformation. This result suggests that the NH2-terminal peptide inhibits binding of plasminogen to fibrin by direct interaction with the fibrin-binding site, and the conformational change that normally accompanies its removal is not a prerequisite of strong binding.

Original languageEnglish
Pages (from-to)6466-6471
Number of pages6
JournalJournal of Biological Chemistry
Volume259
Issue number10
Publication statusPublished - 1984

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Plasminogen
Fibrin
Chemical activation
Kringles
Binding Sites
Peptides
Lysine
Conformations
Light
Urokinase-Type Plasminogen Activator
Tissue Plasminogen Activator
Melanoma
Ligands

ASJC Scopus subject areas

  • Biochemistry

Cite this

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title = "Importance of intramolecular interactions in the control of the fibrin affinity and activation of human plasminogen",
abstract = "Incubation of human Glu-plasminogen with 1,5-difluoro-2,4-dinitrobenzene leads to the specific intramolecular cross-linking of the kringle 1+2+3 region and the light (B) chain region of plasminogen. This cross-link was found to prevent the conformational change which is induced in Glu-plasminogen by lysine analogues or by proteolytic removal of the N2-terminal peptide. Our results suggest that the cross-link freezes the closed conformation of Glu-plasminogen, and it seems likely that the transition to the loose conformer requires separation of the kringle 1+2+3 region from the light (B) chain portion. The change in the relative position of these regions during the conformational change in plasminogen is also indicated by our observation that the rate of formation of the intramolecular cross-link is significantly decreased when transition to the loose conformer is induced either by saturation or the lysine-binding sites or by conversion to Lys-plasminogen. Cross-linked Glu-plasminogen is slowly activated by urokinase and melanoma tissue plasminogen activator, but in contrast with uncross-linked Glu-plasminogen conversion to Lys-plasminogen or saturation of lysine-binding sites with ligand does not increase the rate of activation because the cross-link prevents transition to the loose conformer wich is susceptible to activation. The fibrin affinity of cross-linked Glu-plasminogen is practically identical with that of Glu-plasminogen. As in the case of uncross-linked Glu-plasminogen, removal of the NH2-terminal peptide causes a marked increase in fibrin affinity although the resulting cross-linked Lys-plasminogen is fixed in the closed conformation. This result suggests that the NH2-terminal peptide inhibits binding of plasminogen to fibrin by direct interaction with the fibrin-binding site, and the conformational change that normally accompanies its removal is not a prerequisite of strong binding.",
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T1 - Importance of intramolecular interactions in the control of the fibrin affinity and activation of human plasminogen

AU - Bányai, L.

AU - Patthy, L.

PY - 1984

Y1 - 1984

N2 - Incubation of human Glu-plasminogen with 1,5-difluoro-2,4-dinitrobenzene leads to the specific intramolecular cross-linking of the kringle 1+2+3 region and the light (B) chain region of plasminogen. This cross-link was found to prevent the conformational change which is induced in Glu-plasminogen by lysine analogues or by proteolytic removal of the N2-terminal peptide. Our results suggest that the cross-link freezes the closed conformation of Glu-plasminogen, and it seems likely that the transition to the loose conformer requires separation of the kringle 1+2+3 region from the light (B) chain portion. The change in the relative position of these regions during the conformational change in plasminogen is also indicated by our observation that the rate of formation of the intramolecular cross-link is significantly decreased when transition to the loose conformer is induced either by saturation or the lysine-binding sites or by conversion to Lys-plasminogen. Cross-linked Glu-plasminogen is slowly activated by urokinase and melanoma tissue plasminogen activator, but in contrast with uncross-linked Glu-plasminogen conversion to Lys-plasminogen or saturation of lysine-binding sites with ligand does not increase the rate of activation because the cross-link prevents transition to the loose conformer wich is susceptible to activation. The fibrin affinity of cross-linked Glu-plasminogen is practically identical with that of Glu-plasminogen. As in the case of uncross-linked Glu-plasminogen, removal of the NH2-terminal peptide causes a marked increase in fibrin affinity although the resulting cross-linked Lys-plasminogen is fixed in the closed conformation. This result suggests that the NH2-terminal peptide inhibits binding of plasminogen to fibrin by direct interaction with the fibrin-binding site, and the conformational change that normally accompanies its removal is not a prerequisite of strong binding.

AB - Incubation of human Glu-plasminogen with 1,5-difluoro-2,4-dinitrobenzene leads to the specific intramolecular cross-linking of the kringle 1+2+3 region and the light (B) chain region of plasminogen. This cross-link was found to prevent the conformational change which is induced in Glu-plasminogen by lysine analogues or by proteolytic removal of the N2-terminal peptide. Our results suggest that the cross-link freezes the closed conformation of Glu-plasminogen, and it seems likely that the transition to the loose conformer requires separation of the kringle 1+2+3 region from the light (B) chain portion. The change in the relative position of these regions during the conformational change in plasminogen is also indicated by our observation that the rate of formation of the intramolecular cross-link is significantly decreased when transition to the loose conformer is induced either by saturation or the lysine-binding sites or by conversion to Lys-plasminogen. Cross-linked Glu-plasminogen is slowly activated by urokinase and melanoma tissue plasminogen activator, but in contrast with uncross-linked Glu-plasminogen conversion to Lys-plasminogen or saturation of lysine-binding sites with ligand does not increase the rate of activation because the cross-link prevents transition to the loose conformer wich is susceptible to activation. The fibrin affinity of cross-linked Glu-plasminogen is practically identical with that of Glu-plasminogen. As in the case of uncross-linked Glu-plasminogen, removal of the NH2-terminal peptide causes a marked increase in fibrin affinity although the resulting cross-linked Lys-plasminogen is fixed in the closed conformation. This result suggests that the NH2-terminal peptide inhibits binding of plasminogen to fibrin by direct interaction with the fibrin-binding site, and the conformational change that normally accompanies its removal is not a prerequisite of strong binding.

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VL - 259

SP - 6466

EP - 6471

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JF - Journal of Biological Chemistry

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