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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sg-ntu-dr.10356-1614482023-02-28T17:11:12Z Amyloid β chaperone — lipocalin-type prostaglandin D synthase acts as a peroxidase in the presence of heme Phillips, Margaret Kannaian, Bhuvaneswari Ng, Justin Tze-Yang Kather, Ralf Mu, Yuguang Harmer, Jeffrey R. Pervushin, Konstantin School of Biological Sciences Science::Biological sciences Electron-Paramagnetic-Resonance Site-Directed Mutagenesis 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. Ministry of Education (MOE) Published version The research for this paper was supported by the MOE-Tier 2 grant M4020231. J.R.H. acknowledges support from the ARC (FT120100421). 2022-09-02T05:11:06Z 2022-09-02T05:11:06Z 2020 Journal Article Phillips, M., Kannaian, B., Ng, J. T., Kather, R., Mu, Y., Harmer, J. R. & Pervushin, K. (2020). Amyloid β chaperone — lipocalin-type prostaglandin D synthase acts as a peroxidase in the presence of heme. Biochemical Journal, 477(7), 1227-1240. https://dx.doi.org/10.1042/BCJ20190536 0264-6021 https://hdl.handle.net/10356/161448 10.1042/BCJ20190536 32271881 2-s2.0-85087026464 7 477 1227 1240 en M4020231 Biochemical Journal © 2020 The Author(s). 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). application/pdf |
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Science::Biological sciences Electron-Paramagnetic-Resonance Site-Directed Mutagenesis Phillips, Margaret Kannaian, Bhuvaneswari Ng, Justin Tze-Yang Kather, Ralf Mu, Yuguang Harmer, Jeffrey R. Pervushin, Konstantin Amyloid β chaperone — lipocalin-type prostaglandin D synthase acts as a peroxidase in the presence of heme |
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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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School of Biological Sciences |
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School of Biological Sciences Phillips, Margaret Kannaian, Bhuvaneswari Ng, Justin Tze-Yang Kather, Ralf Mu, Yuguang Harmer, Jeffrey R. Pervushin, Konstantin |
format |
Article |
author |
Phillips, Margaret Kannaian, Bhuvaneswari Ng, Justin Tze-Yang Kather, Ralf Mu, Yuguang Harmer, Jeffrey R. Pervushin, Konstantin |
author_sort |
Phillips, Margaret |
title |
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_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_sort |
amyloid β chaperone — lipocalin-type prostaglandin d synthase acts as a peroxidase in the presence of heme |
publishDate |
2022 |
url |
https://hdl.handle.net/10356/161448 |
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1759854275309076480 |