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Amyloid β chaperone — lipocalin-type prostaglandin D synthase acts as a peroxidase in the presence of heme
The extracellular transporter, lipocalin-type prostaglandin D synthase (L-PGDS) binds to heme and heme metabolites with high affinity. It has been reported that L-PGDS protects neuronal cells against apoptosis induced by exposure to hydrogen peroxide. Our study demonstrates that when human WT L-PGDS...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Portland Press Ltd.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148433/ https://www.ncbi.nlm.nih.gov/pubmed/32271881 http://dx.doi.org/10.1042/BCJ20190536 |
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author | Phillips, Margaret Kannaian, Bhuvaneswari Yang, Justin Ng Tze Kather, Ralf Yuguang, Mu Harmer, Jeffrey R. Pervushin, Konstantin |
author_facet | Phillips, Margaret Kannaian, Bhuvaneswari Yang, Justin Ng Tze Kather, Ralf Yuguang, Mu Harmer, Jeffrey R. Pervushin, Konstantin |
author_sort | Phillips, Margaret |
collection | PubMed |
description | The extracellular transporter, lipocalin-type prostaglandin D synthase (L-PGDS) binds to heme and heme metabolites with high affinity. It has been reported that L-PGDS protects neuronal cells against apoptosis induced by exposure to hydrogen peroxide. Our study demonstrates that when human WT L-PGDS is in complex with heme, it exhibits a strong peroxidase activity thus behaving as a pseudo-peroxidase. Electron paramagnetic resonance studies confirm that heme in the L-PGDS–heme complex is hexacoordinated with high-spin Fe(III). NMR titration of heme in L-PGDS points to hydrophobic interaction between heme and several residues within the β-barrel cavity of L-PGDS. In addition to the transporter function, L-PGDS is a key amyloid β chaperone in human cerebrospinal fluid. The presence of high levels of bilirubin and its derivatives, implicated in Alzheimer's disease, by binding to L-PGDS may reduce its chaperone activity. Nevertheless, our ThT binding assay establishes that heme and heme metabolites do not significantly alter the neuroprotective chaperone function of L-PGDS. Guided by NMR data we reconstructed the heme L-PGDS complex using extensive molecular dynamics simulations providing a platform for mechanistic interpretation of the catalytic and transporting functions and their modulation by secondary ligands like Aβ peptides and heme metabolites. |
format | Online Article Text |
id | pubmed-7148433 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-71484332020-04-17 Amyloid β chaperone — lipocalin-type prostaglandin D synthase acts as a peroxidase in the presence of heme Phillips, Margaret Kannaian, Bhuvaneswari Yang, Justin Ng Tze Kather, Ralf Yuguang, Mu Harmer, Jeffrey R. Pervushin, Konstantin Biochem J Structural Biology The extracellular transporter, lipocalin-type prostaglandin D synthase (L-PGDS) binds to heme and heme metabolites with high affinity. It has been reported that L-PGDS protects neuronal cells against apoptosis induced by exposure to hydrogen peroxide. Our study demonstrates that when human WT L-PGDS is in complex with heme, it exhibits a strong peroxidase activity thus behaving as a pseudo-peroxidase. Electron paramagnetic resonance studies confirm that heme in the L-PGDS–heme complex is hexacoordinated with high-spin Fe(III). NMR titration of heme in L-PGDS points to hydrophobic interaction between heme and several residues within the β-barrel cavity of L-PGDS. In addition to the transporter function, L-PGDS is a key amyloid β chaperone in human cerebrospinal fluid. The presence of high levels of bilirubin and its derivatives, implicated in Alzheimer's disease, by binding to L-PGDS may reduce its chaperone activity. Nevertheless, our ThT binding assay establishes that heme and heme metabolites do not significantly alter the neuroprotective chaperone function of L-PGDS. Guided by NMR data we reconstructed the heme L-PGDS complex using extensive molecular dynamics simulations providing a platform for mechanistic interpretation of the catalytic and transporting functions and their modulation by secondary ligands like Aβ peptides and heme metabolites. Portland Press Ltd. 2020-04-17 2020-04-09 /pmc/articles/PMC7148433/ /pubmed/32271881 http://dx.doi.org/10.1042/BCJ20190536 Text en © 2020 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Structural Biology Phillips, Margaret Kannaian, Bhuvaneswari Yang, Justin Ng Tze Kather, Ralf Yuguang, Mu Harmer, Jeffrey R. Pervushin, Konstantin Amyloid β chaperone — lipocalin-type prostaglandin D synthase acts as a peroxidase in the presence of heme |
title | Amyloid β chaperone — lipocalin-type prostaglandin D synthase acts as a peroxidase in the presence of heme |
title_full | Amyloid β chaperone — lipocalin-type prostaglandin D synthase acts as a peroxidase in the presence of heme |
title_fullStr | Amyloid β chaperone — lipocalin-type prostaglandin D synthase acts as a peroxidase in the presence of heme |
title_full_unstemmed | Amyloid β chaperone — lipocalin-type prostaglandin D synthase acts as a peroxidase in the presence of heme |
title_short | Amyloid β chaperone — lipocalin-type prostaglandin D synthase acts as a peroxidase in the presence of heme |
title_sort | amyloid β chaperone — lipocalin-type prostaglandin d synthase acts as a peroxidase in the presence of heme |
topic | Structural Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148433/ https://www.ncbi.nlm.nih.gov/pubmed/32271881 http://dx.doi.org/10.1042/BCJ20190536 |
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