Abundant neuroprotective chaperone Lipocalin-type prostaglandin D synthase (L-PGDS) disassembles the Amyloid-β fibrils
Misfolding of Amyloid β (Aβ) peptides leads to the formation of extracellular amyloid plaques. Molecular chaperones can facilitate the refolding or degradation of such misfolded proteins. Here, for the first time, we report the unique ability of Lipocalin-type Prostaglandin D synthase (L-PGDS) prote...
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| creator | Kannaian, Bhuvaneswari Sharma, Bhargy Phillips, Margaret Chowdhury, Anup Manimekalai, Malathy S. S. Adav, Sunil S. Ng, Justin T. Y. Kumar, Ambrish Lim, Sierin Mu, Yuguang Sze, Siu K. Grüber, Gerhard Pervushin, Konstantin |
| description | Misfolding of Amyloid β (Aβ) peptides leads to the formation of extracellular amyloid plaques. Molecular chaperones can facilitate the refolding or degradation of such misfolded proteins. Here, for the first time, we report the unique ability of Lipocalin-type Prostaglandin D synthase (L-PGDS) protein to act as a disaggregase on the pre-formed fibrils of Aβ(1–40), abbreviated as Aβ40, and Aβ(25–35) peptides, in addition to inhibiting the aggregation of Aβ monomers. Furthermore, our proteomics results indicate that L-PGDS can facilitate extraction of several other proteins from the insoluble aggregates extracted from the brain of an Alzheimer’s disease patient. In this study, we have established the mode of binding of L-PGDS with monomeric and fibrillar Aβ using Nuclear Magnetic Resonance (NMR) Spectroscopy, Small Angle X-ray Scattering (SAXS), and Transmission Electron Microscopy (TEM). Our results confirm a direct interaction between L-PGDS and monomeric Aβ40 and Aβ(25–35), thereby inhibiting their spontaneous aggregation. The monomeric unstructured Aβ40 binds to L-PGDS via its C-terminus, while the N-terminus remains free which is observed as a new domain in the L-PGDS-Aβ40 complex model. |
| doi_str_mv | 10.1038/s41598-019-48819-5 |
| format | Article |
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S. ; Adav, Sunil S. ; Ng, Justin T. Y. ; Kumar, Ambrish ; Lim, Sierin ; Mu, Yuguang ; Sze, Siu K. ; Grüber, Gerhard ; Pervushin, Konstantin</creator><creatorcontrib>Kannaian, Bhuvaneswari ; Sharma, Bhargy ; Phillips, Margaret ; Chowdhury, Anup ; Manimekalai, Malathy S. S. ; Adav, Sunil S. ; Ng, Justin T. Y. ; Kumar, Ambrish ; Lim, Sierin ; Mu, Yuguang ; Sze, Siu K. ; Grüber, Gerhard ; Pervushin, Konstantin</creatorcontrib><description>Misfolding of Amyloid β (Aβ) peptides leads to the formation of extracellular amyloid plaques. Molecular chaperones can facilitate the refolding or degradation of such misfolded proteins. Here, for the first time, we report the unique ability of Lipocalin-type Prostaglandin D synthase (L-PGDS) protein to act as a disaggregase on the pre-formed fibrils of Aβ(1–40), abbreviated as Aβ40, and Aβ(25–35) peptides, in addition to inhibiting the aggregation of Aβ monomers. Furthermore, our proteomics results indicate that L-PGDS can facilitate extraction of several other proteins from the insoluble aggregates extracted from the brain of an Alzheimer’s disease patient. In this study, we have established the mode of binding of L-PGDS with monomeric and fibrillar Aβ using Nuclear Magnetic Resonance (NMR) Spectroscopy, Small Angle X-ray Scattering (SAXS), and Transmission Electron Microscopy (TEM). Our results confirm a direct interaction between L-PGDS and monomeric Aβ40 and Aβ(25–35), thereby inhibiting their spontaneous aggregation. The monomeric unstructured Aβ40 binds to L-PGDS via its C-terminus, while the N-terminus remains free which is observed as a new domain in the L-PGDS-Aβ40 complex model.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-019-48819-5</identifier><identifier>PMID: 31467325</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>101/28 ; 101/58 ; 101/6 ; 631/337/470/1981 ; 631/535 ; 82 ; 82/83 ; Amyloid ; Amyloid beta-Peptides - chemistry ; Amyloid beta-Peptides - metabolism ; C-Terminus ; Chaperones ; Fibrils ; Humanities and Social Sciences ; Humans ; Intramolecular Oxidoreductases - metabolism ; Lipocalin ; Lipocalins - metabolism ; Molecular Chaperones - metabolism ; Monomers ; multidisciplinary ; N-Terminus ; Neuroprotection ; NMR ; Nuclear magnetic resonance ; Peptide Fragments - chemistry ; Peptide Fragments - metabolism ; Peptides ; Prostaglandin D2 synthase ; Protein Aggregates ; Protein Domains ; Protein folding ; Proteomics ; Science ; Science (multidisciplinary) ; Senile plaques ; Spectroscopy ; Transmission electron microscopy ; X-ray scattering</subject><ispartof>Scientific reports, 2019-08, Vol.9 (1), p.12579-17, Article 12579</ispartof><rights>The Author(s) 2019</rights><rights>2019. 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S.</au><au>Adav, Sunil S.</au><au>Ng, Justin T. Y.</au><au>Kumar, Ambrish</au><au>Lim, Sierin</au><au>Mu, Yuguang</au><au>Sze, Siu K.</au><au>Grüber, Gerhard</au><au>Pervushin, Konstantin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Abundant neuroprotective chaperone Lipocalin-type prostaglandin D synthase (L-PGDS) disassembles the Amyloid-β fibrils</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2019-08-29</date><risdate>2019</risdate><volume>9</volume><issue>1</issue><spage>12579</spage><epage>17</epage><pages>12579-17</pages><artnum>12579</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Misfolding of Amyloid β (Aβ) peptides leads to the formation of extracellular amyloid plaques. Molecular chaperones can facilitate the refolding or degradation of such misfolded proteins. Here, for the first time, we report the unique ability of Lipocalin-type Prostaglandin D synthase (L-PGDS) protein to act as a disaggregase on the pre-formed fibrils of Aβ(1–40), abbreviated as Aβ40, and Aβ(25–35) peptides, in addition to inhibiting the aggregation of Aβ monomers. Furthermore, our proteomics results indicate that L-PGDS can facilitate extraction of several other proteins from the insoluble aggregates extracted from the brain of an Alzheimer’s disease patient. In this study, we have established the mode of binding of L-PGDS with monomeric and fibrillar Aβ using Nuclear Magnetic Resonance (NMR) Spectroscopy, Small Angle X-ray Scattering (SAXS), and Transmission Electron Microscopy (TEM). Our results confirm a direct interaction between L-PGDS and monomeric Aβ40 and Aβ(25–35), thereby inhibiting their spontaneous aggregation. The monomeric unstructured Aβ40 binds to L-PGDS via its C-terminus, while the N-terminus remains free which is observed as a new domain in the L-PGDS-Aβ40 complex model.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31467325</pmid><doi>10.1038/s41598-019-48819-5</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0001-7455-6771</orcidid><orcidid>https://orcid.org/0000-0002-5652-1687</orcidid><orcidid>https://orcid.org/0000-0002-8559-4885</orcidid><orcidid>https://orcid.org/0000-0002-9693-7791</orcidid><orcidid>https://orcid.org/0000-0002-2499-026X</orcidid><orcidid>https://orcid.org/0000-0003-2713-8563</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 101/28 101/58 101/6 631/337/470/1981 631/535 82 82/83 Amyloid Amyloid beta-Peptides - chemistry Amyloid beta-Peptides - metabolism C-Terminus Chaperones Fibrils Humanities and Social Sciences Humans Intramolecular Oxidoreductases - metabolism Lipocalin Lipocalins - metabolism Molecular Chaperones - metabolism Monomers multidisciplinary N-Terminus Neuroprotection NMR Nuclear magnetic resonance Peptide Fragments - chemistry Peptide Fragments - metabolism Peptides Prostaglandin D2 synthase Protein Aggregates Protein Domains Protein folding Proteomics Science Science (multidisciplinary) Senile plaques Spectroscopy Transmission electron microscopy X-ray scattering |
| title | Abundant neuroprotective chaperone Lipocalin-type prostaglandin D synthase (L-PGDS) disassembles the Amyloid-β fibrils |
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