Arg177 and Asp159 from dog prion protein slow liquid-liquid phase separation and inhibit amyloid formation of human prion protein
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved..
Prion diseases are a group of transmissible neurodegenerative diseases primarily caused by the conformational conversion of prion protein (PrP) from α-helix-dominant cellular prion protein (PrPC) to β-sheet-rich pathological aggregated form of PrPSc in many mammalian species. Dogs exhibit resistance to prion diseases, but the mechanism behind the phenomenon remains poorly understood. Compared with human PrP and mouse PrP, dog PrP has two unique amino acid residues, Arg177 and Asp159. Because PrPC contains a low-complexity and intrinsically disordered region in its N-terminal domain, it undergoes liquid-liquid phase separation (LLPS) in vitro and forms protein condensates. However, little is known about whether these two unique residues modulate the formation of PrPC condensates. Here, using confocal microscopy, fluorescence recovery after photobleaching assays, thioflavin T binding assays, and transmission electron microscopy, we report that Arg177 and Asp159 from the dog PrP slow the LLPS of full-length human PrPC, shifting the equilibrium phase boundary to higher protein concentrations and inhibit amyloid formation of the human protein. In sharp contrast, His177 and Asn159 from the human PrP enhance the LLPS of full-length dog PrPC, shifting the equilibrium phase boundary to lower protein concentrations, and promote fibril formation of the canid protein. Collectively, these results demonstrate how LLPS and amyloid formation of PrP are inhibited by a single residue Arg177 or Asp159 associated with prion disease resistance, and how LLPS and fibril formation of PrP are promoted by a single residue His177 or Asn159. Therefore, Arg177/His177 and Asp159/Asn159 are key residues in modulating PrPC liquid-phase condensation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:299 |
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| Enthalten in: |
The Journal of biological chemistry - 299(2023), 11 vom: 01. Nov., Seite 105329 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Xiang-Ning [VerfasserIn] |
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| Links: |
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| Themen: |
Amyloid |
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| Anmerkungen: |
Date Completed 27.11.2023 Date Revised 27.11.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jbc.2023.105329 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM362987300 |
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| 024 | 7 | |a 10.1016/j.jbc.2023.105329 |2 doi | |
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| 035 | |a (NLM)37805139 | ||
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| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Li, Xiang-Ning |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Arg177 and Asp159 from dog prion protein slow liquid-liquid phase separation and inhibit amyloid formation of human prion protein |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 27.11.2023 | ||
| 500 | |a Date Revised 27.11.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Prion diseases are a group of transmissible neurodegenerative diseases primarily caused by the conformational conversion of prion protein (PrP) from α-helix-dominant cellular prion protein (PrPC) to β-sheet-rich pathological aggregated form of PrPSc in many mammalian species. Dogs exhibit resistance to prion diseases, but the mechanism behind the phenomenon remains poorly understood. Compared with human PrP and mouse PrP, dog PrP has two unique amino acid residues, Arg177 and Asp159. Because PrPC contains a low-complexity and intrinsically disordered region in its N-terminal domain, it undergoes liquid-liquid phase separation (LLPS) in vitro and forms protein condensates. However, little is known about whether these two unique residues modulate the formation of PrPC condensates. Here, using confocal microscopy, fluorescence recovery after photobleaching assays, thioflavin T binding assays, and transmission electron microscopy, we report that Arg177 and Asp159 from the dog PrP slow the LLPS of full-length human PrPC, shifting the equilibrium phase boundary to higher protein concentrations and inhibit amyloid formation of the human protein. In sharp contrast, His177 and Asn159 from the human PrP enhance the LLPS of full-length dog PrPC, shifting the equilibrium phase boundary to lower protein concentrations, and promote fibril formation of the canid protein. Collectively, these results demonstrate how LLPS and amyloid formation of PrP are inhibited by a single residue Arg177 or Asp159 associated with prion disease resistance, and how LLPS and fibril formation of PrP are promoted by a single residue His177 or Asn159. Therefore, Arg177/His177 and Asp159/Asn159 are key residues in modulating PrPC liquid-phase condensation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a dog prion protein | |
| 650 | 4 | |a prion disease resistance | |
| 650 | 4 | |a prion diseases | |
| 650 | 4 | |a prion protein | |
| 650 | 4 | |a protein aggregation | |
| 650 | 4 | |a protein liquid–liquid phase separation | |
| 650 | 7 | |a Prion Proteins |2 NLM | |
| 650 | 7 | |a Prions |2 NLM | |
| 650 | 7 | |a Amyloid |2 NLM | |
| 650 | 7 | |a Amyloidogenic Proteins |2 NLM | |
| 700 | 1 | |a Gao, Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Yin, Jin-Xu |e verfasserin |4 aut | |
| 700 | 1 | |a Yi, Chuan-Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Han-Ye |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Jun-Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Li-Qiang |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Yi |e verfasserin |4 aut | |
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| 773 | 1 | 8 | |g volume:299 |g year:2023 |g number:11 |g day:01 |g month:11 |g pages:105329 |
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