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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...

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Autores principales: Phillips, Margaret, Kannaian, Bhuvaneswari, Yang, Justin Ng Tze, Kather, Ralf, Yuguang, Mu, Harmer, Jeffrey R., Pervushin, Konstantin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2020
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.
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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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