Liquid–liquid phase separation of the prion protein is regulated by the octarepeat domain independently of histidines and copper

Kamps, Janine; Bader, Verian; Winklhofer, Konstanze F.; Tatzelt, Jörg

doi:10.1016/j.jbc.2024.107310

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Journal of Biological Chemistry

2024

DOI: 10.1016/j.jbc.2024.107310

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Liquid–liquid phase separation of the prion protein is regulated by the octarepeat domain independently of histidines and copper

Janine Kamps,

Verian Bader,

Konstanze F. Winklhofer

et al.

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2024

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Cited by 3 publications

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Amino acid-dependent phase equilibrium and material properties of tetrapeptide condensates

Zhang,

Prasad,

et al. 2024

Cell Reports Physical Science

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Amino acid-dependent phase equilibrium and material properties of tetrapeptide condensates

Zhang,

Prasad,

et al. 2024

Cell Reports Physical Science

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Unfolding Mechanism and Fibril Formation Propensity of Human Prion Protein in the Presence of Molecular Crowding Agents

Madheswaran,

Ventserova,

D’Abrosca

et al. 2024

IJMS

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The pathological process of prion diseases implicates that the normal physiological cellular prion protein (PrPC) converts into misfolded abnormal scrapie prion (PrPSc) through post-translational modifications that increase β-sheet conformation. We recently demonstrated that HuPrP(90–231) thermal unfolding is partially irreversible and characterized by an intermediate state (β-PrPI), which has been revealed to be involved in the initial stages of PrPC fibrillation, with a seeding activity comparable to that of human infectious prions. In this study, we report the thermal unfolding characterization, in cell-mimicking conditions, of the truncated (HuPrP(90–231)) and full-length (HuPrP(23–231)) human prion protein by means of CD and NMR spectroscopy, revealing that HuPrP(90–231) thermal unfolding is characterized by two successive transitions, as in buffer solution. The amyloidogenic propensity of HuPrP(90–231) under crowded conditions has also been investigated. Our findings show that although the prion intermediate, structurally very similar to β-PrPI, forms at a lower temperature compared to when it is dissolved in buffer solution, in cell-mimicking conditions, the formation of prion fibrils requires a longer incubation time, outlining how molecular crowding influences both the equilibrium states of PrP and its kinetic pathways of folding and aggregation.

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1-L Transcription in Prion Diseases

Nahalka

2024

IJMS

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Understanding the pathogenesis and mechanisms of prion diseases can significantly expand our knowledge in the field of neurodegenerative diseases. Prion biology is increasingly recognized as being relevant to the pathophysiology of Alzheimer’s disease and Parkinson’s disease, both of which affect millions of people each year. This bioinformatics study used a theoretical protein-RNA recognition code (1-L transcription) to reveal the post-transcriptional regulation of the prion protein (PrPC). The principle for this method is directly elucidated on PrPC, in which an octa-repeat can be 1-L transcribed into a GGA triplet repeat RNA aptamer known to reduce the misfolding of normal PrPC into abnormal PrPSc. The identified genes/proteins are associated with mitochondria, cancer, COVID-19 and ER-stress, and approximately half are directly or indirectly associated with prion diseases. For example, the octa-repeat supports CD44, and regions of the brain with astrocytic prion accumulation also display high levels of CD44.

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Liquid–liquid phase separation of the prion protein is regulated by the octarepeat domain independently of histidines and copper

Cited by 3 publications

References 58 publications

Amino acid-dependent phase equilibrium and material properties of tetrapeptide condensates

Amino acid-dependent phase equilibrium and material properties of tetrapeptide condensates

Unfolding Mechanism and Fibril Formation Propensity of Human Prion Protein in the Presence of Molecular Crowding Agents

1-L Transcription in Prion Diseases

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