Enthalpy measurement using calorimetry shows a significant difference in potential energy between the active and latent conformations of PAI-1

Enthalpy measurement using calorimetry shows a significant difference in potential energy between... Abstract A central feature of the serpin inhibition mechanism is insertion of the reactive center loop into the central β-sheet (β-sheet A). This insertion also occurs when the reactive center loop is cleaved without protease inhibition. Using this effect, we have measured the enthalpy (ΔH) of loop cleavage and insertion for plasminogen activator inhibitor 1 (PAI-1) as -38 kcal/mol. Because loop insertion can be blocked by incorporating a peptide into the central β-sheet, it was possible to assign -7 kcal/mol to loop cleavage and -31 kcal/mol to loop insertion. These values are lower than values reported for the serpins α 1 -proteinase inhibitor and antithrombin of -53 to -63 kcal/mol, respectively, for loop insertion with negligible enthalpy for loop cleavage. A free energy difference of -9 kcal/mol has been reported between the active and spontaneously loop inserted ‘latent forms’ of PAI-1, which is significantly smaller in magnitude than the -31 kcal/mol of enthalpy we measured for loop insertion. Because the enthalpy should relate closely to those regions of PAI-1 that have moved to lower potential energy, a difference distance matrix is presented that identifies regions of PAI-1 that move during loop insertion. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Biological Chemistry de Gruyter

Enthalpy measurement using calorimetry shows a significant difference in potential energy between the active and latent conformations of PAI-1

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Publisher
de Gruyter
Copyright
Copyright © 2005 by the
ISSN
1431-6730
eISSN
1437-4315
DOI
10.1515/BC.2005.014
pmid
15843154
Publisher site
See Article on Publisher Site

Abstract

Abstract A central feature of the serpin inhibition mechanism is insertion of the reactive center loop into the central β-sheet (β-sheet A). This insertion also occurs when the reactive center loop is cleaved without protease inhibition. Using this effect, we have measured the enthalpy (ΔH) of loop cleavage and insertion for plasminogen activator inhibitor 1 (PAI-1) as -38 kcal/mol. Because loop insertion can be blocked by incorporating a peptide into the central β-sheet, it was possible to assign -7 kcal/mol to loop cleavage and -31 kcal/mol to loop insertion. These values are lower than values reported for the serpins α 1 -proteinase inhibitor and antithrombin of -53 to -63 kcal/mol, respectively, for loop insertion with negligible enthalpy for loop cleavage. A free energy difference of -9 kcal/mol has been reported between the active and spontaneously loop inserted ‘latent forms’ of PAI-1, which is significantly smaller in magnitude than the -31 kcal/mol of enthalpy we measured for loop insertion. Because the enthalpy should relate closely to those regions of PAI-1 that have moved to lower potential energy, a difference distance matrix is presented that identifies regions of PAI-1 that move during loop insertion.

Journal

Biological Chemistryde Gruyter

Published: Feb 1, 2005

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