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https://hdl.handle.net/2440/129449
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Type: | Journal article |
Title: | Pyrexia and acidosis act independently of neutrophil elastase reactive center loop cleavage to effect cortisol release from corticosteroid-binding globulin |
Author: | Meyer, E.J. Torpy, D.J. Chernykh, A. Thaysen-Andersen, M. Nenke, M.A. Lewis, J. Rajapaksha, H. Rankin, W. Polyak, S.W. |
Citation: | Protein Science, 2020; 29(12):2495-2509 |
Publisher: | Wiley |
Issue Date: | 2020 |
ISSN: | 0961-8368 1469-896X |
Statement of Responsibility: | Emily J. Meyer, David J. Torpy, Anastasia Chernykh, Morten Thaysen-Andersen, Marni A. Nenke, John G. Lewis, Harinda Rajapaksha, Wayne Rankin, Steven W. Polyak |
Abstract: | Corticosteroid-binding globulin (CBG) transports cortisol and other steroids. High-affinity CBG (haCBG) undergoes proteolysis of the reactive center loop (RCL) by neutrophil elastase (NE) altering conformation to low-affinity CBG (laCBG). Elevated temperature reduces CBG:cortisol binding affinity. Surface plasmon resonance was used to determine binding profiles of 19 steroids to haCBG and laCBG at 25°C, 37°C and 39°C mimicking pyrexia and pH 7.4 and 7.0 mimicking acidosis, pathophysiological conditions relevant to sepsis. An expected 4-8-fold reduction in affinity for cortisol, cortisone, corticosterone, 11-deoxycortisol, progesterone, 17-hydroxyprogesterone and prednisolone occurred with NE-mediated haCBG-to-laCBG conversion. CBG:cortisol binding affinity was further reduced 3.5-fold at 39°C relative to 37°C, binding affinity was also reduced by acidosis for both haCBG and laCBG. Using a conformational antibody generated against the RCL, we confirmed RCL antibody binding was eliminated by NE cleavage, but preserved in pyrexia and acidosis. Molecular modelling studies performed at 40°C confirmed a critical role for Trp371, positioned within the steroid-binding pocket, in ligand binding. These studies demonstrated CBG binding affinity to range of steroids is ligand specific and is reduced with NE-mediated haCBG-to-laCBG transition. Reduced CBG:cortisol binding occurs with increased temperature and in acidosis. Increased flexibility of the Trp371 side chain is proposed in the thermo-coupling mechanism of cortisol release. The synergy of NE cleavage, pyrexia and acidosis on CBG:cortisol binding may serve to enhance cortisol delivery to the interstitial space in inflammation. |
Keywords: | Acidemia; corticosteroid-binding globulin; cortisol; ligand binding affinity; pyrexia |
Rights: | © 2020 The Protein Society |
DOI: | 10.1002/pro.3982 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1147538 |
Published version: | http://dx.doi.org/10.1002/pro.3982 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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