Please use this identifier to cite or link to this item:
http://hdl.handle.net/123456789/4396
Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Agarwal, Aishwarya | - |
dc.contributor.author | K. Rai, Sandeep | - |
dc.contributor.author | Avni, Anamika | - |
dc.contributor.author | Mukhopadhyay, Samrat | - |
dc.date.accessioned | 2023-08-08T17:52:42Z | - |
dc.date.available | 2023-08-08T17:52:42Z | - |
dc.date.issued | 2021 | - |
dc.identifier.citation | Proceedings of the National Academy of Sciences of the United States of America, 118(45). | en_US |
dc.identifier.uri | https://doi.org/10.1073/pnas.2100968118 | - |
dc.identifier.uri | http://hdl.handle.net/123456789/4396 | - |
dc.description | Only IISER Mohali authors are available in the record. | en_US |
dc.description.abstract | Biomolecular condensation via liquid–liquid phase separation of intrinsically disordered proteins/regions (IDPs/IDRs) along with other biomolecules is proposed to control critical cellular functions, whereas aberrant phase transitions are associated with a range of neurodegenerative diseases. Here, we show that a disease-associated stop codon mutation of the prion protein (PrP) at tyrosine 145 (Y145Stop), resulting in a truncated, highly disordered, N-terminal IDR, spontaneously phase-separates into dynamic liquid-like droplets. Phase separation of this highly positively charged N-terminal segment is promoted by the electrostatic screening and a multitude of weak, transient, multivalent, intermolecular interactions. Single-droplet Raman measurements, in conjunction with an array of bioinformatic, spectroscopic, microscopic, and mutagenesis studies, revealed a highly mobile internal organization within the liquid-like condensates. The phase behavior of Y145Stop is modulated by RNA. Lower RNA:protein ratios promote condensation at a low micromolar protein concentration under physiological conditions. At higher concentrations of RNA, phase separation is abolished. Upon aging, these highly dynamic liquid-like droplets gradually transform into ordered, β-rich, amyloid-like aggregates. These aggregates formed via phase transitions display an autocatalytic self-templating characteristic involving the recruitment and binding-induced conformational conversion of monomeric Y145Stop into amyloid fibrils. In contrast to this intrinsically disordered truncated variant, the wild-type full-length PrP exhibits a much lower propensity for both condensation and maturation into amyloids, hinting at a possible protective role of the C-terminal domain. Such an interplay of molecular factors in modulating the protein phase behavior might have much broader implications in cell physiology and disease. | en_US |
dc.language.iso | en_US | en_US |
dc.publisher | PNAS | en_US |
dc.subject | An intrinsically | en_US |
dc.subject | disordered pathological prion | en_US |
dc.subject | variant Y145Stop | en_US |
dc.subject | amyloids | en_US |
dc.title | An intrinsically disordered pathological prion variant Y145Stop converts into self-seeding amyloids via liquid–liquid phase separation | en_US |
dc.type | Article | en_US |
Appears in Collections: | Research Articles |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
Need To Add…Full Text_PDF..pdf | Only IISER Mohali authors are available in the record. | 15.36 kB | Adobe PDF | View/Open |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.