N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases

Hara, Hideyuki; Sakaguchi, Suehiro

doi:10.3390/ijms21176233

Cited by 19 publications

(15 citation statements)

References 102 publications

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“…126-230) has a highly conserved, mostly helical tertiary structure, with one intramolecular disulfide bond [33,34]. The unstructured N-terminal half possesses several regions involved in specific functions [35]. Among them, the highly conserved hydrophobic domain (HD, aa.…”

Section: Introductionmentioning

confidence: 99%

Membrane Domain Localization and Interaction of the Prion-Family Proteins, Prion and Shadoo with Calnexin

et al. 2021

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The cellular prion protein (PrPC) is renowned for its infectious conformational isoform PrPSc, capable of templating subsequent conversions of healthy PrPCs and thus triggering the group of incurable diseases known as transmissible spongiform encephalopathies. Besides this mechanism not being fully uncovered, the protein’s physiological role is also elusive. PrPC and its newest, less understood paralog Shadoo are glycosylphosphatidylinositol-anchored proteins highly expressed in the central nervous system. While they share some attributes and neuroprotective actions, opposing roles have also been reported for the two; however, the amount of data about their exact functions is lacking. Protein–protein interactions and membrane microdomain localizations are key determinants of protein function. Accurate identification of these functions for a membrane protein, however, can become biased due to interactions occurring during sample processing. To avoid such artifacts, we apply a non-detergent-based membrane-fractionation approach to study the prion protein and Shadoo. We show that the two proteins occupy similarly raft and non-raft membrane fractions when expressed in N2a cells and that both proteins pull down the chaperone calnexin in both rafts and non-rafts. These indicate their possible binding to calnexin in both types of membrane domains, which might be a necessary requisite to aid the inherently unstable native conformation during their lifetime.

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Section: Introductionmentioning

confidence: 99%

Membrane Domain Localization and Interaction of the Prion-Family Proteins, Prion and Shadoo with Calnexin

et al. 2021

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“…1). The FT region, an intrinsic disordered domain, plays a crucial role in the pathogenesis of prion diseases (15). The primary nine polybasic amino acids (23)(24)(25)(26)(27)(28)(29)(30)(31) have been reported as a prerequisite for channel activity of the truncated PrP protein (∆CR PrP with 105-125 amino acids deleted) (11,12).…”

Section: Introductionmentioning

confidence: 99%

The channel activities of the full-length prion and truncated proteins

Lakkaraju

Aguzzi

et al. 2022

Preprint

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Prion disease is a fatal neurodegenerative disorder, in which the cellular prion protein PrPC is converted to a misfolded prion which in turn is hypothesized to permeabilize cellular membranes. The pathways leading to toxicity in prion disease are not yet completely elucidated and whether it also includes formation of membrane pores remains to be answered. Prion protein consists of two domains: a globular domain (GD) and a flexible N-terminus (FT) domain. Although a proximal nine polybasic amino acid (FT(23-31)) sequence of FT is a prerequisite for cellular membrane permeabilization, other functional domain regions may influence FT(23-31) and its permeabilization. By using single-channel electrical recordings, we reveal that FT(23-50) dominates the membrane permeabilization within the full-length mouse PrP (mPrP(23-230)). The other domain of FT(51-110) or C-terminal domain down-regulates the channel activity of FT(23-50) and the full-length mouse PrP (mPrP(23-230)). The addition of prion mimetic antibody, POM1 significantly enhances mPrP(23-230) membrane permeabilization, whereas POM1-Y104A, a POM1 mutant that binds to PrP but cannot elicit toxicity has negligible effect on membrane permeabilization. Additionally, anti-N-terminal antibody POM2 or Cu2+ stabilizes FT domain, thus provoking FT(23-110) channel activity. Furthermore, our setup provides a more direct method without an external fused protein to study the channel activity of truncated PrP in the lipid membranes. We therefore hypothesize that the primary N-terminal residues are essential for membranes permeabilization and other functional segments play a vital role to modulate the pathological effects of PrP-medicated neurotoxicity. This may yield essential insights into molecular mechanisms of prion neurotoxicity to cellular membranes in prion disease.

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“…Interestingly, several studies have shown that the NPR-which is located at very Nterminus and remains PK-sensitive in PrP Sc -plays a significant role in the pathogenesis of prion disease (21). Several transgenic mice expressing PrP with NPR deletion mutations (oror replacement mutations (replacing 23 KKRPK 28 to J o u r n a l P r e -p r o o f 5 KQHPH or AARPA) were established.…”

Section: Introductionmentioning

confidence: 99%

The protease-sensitive N-terminal polybasic region of prion protein modulates its conversion to the pathogenic prion conformer

Zhang

Pan

Ying

et al. 2021

Journal of Biological Chemistry

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases

Cited by 19 publications

References 102 publications

Membrane Domain Localization and Interaction of the Prion-Family Proteins, Prion and Shadoo with Calnexin

Membrane Domain Localization and Interaction of the Prion-Family Proteins, Prion and Shadoo with Calnexin

The channel activities of the full-length prion and truncated proteins

The protease-sensitive N-terminal polybasic region of prion protein modulates its conversion to the pathogenic prion conformer

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