The possible role of protein X, a putative auxiliary factor in pathological prion replication, in regulating a physiological endoproteolytic cleavage of cellular prion protein

Hachiya, Naomi; Imagawa, Midori; Kaneko, Kiyotoshi

doi:10.1016/j.mehy.2006.07.038

Cited by 10 publications

(7 citation statements)

References 38 publications

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“…Some studies have shown that PrP-lipid interactions can influence PrP conformation (53,146,147), therefore the PrP lipid environment has the potential to influence the PrP C to PrP Sc conversion process. One hypothesis states that potential molecular chaperones which might mediate PrP C unfolding to allow, for example, biologically relevant endogenous cleavage, could have an inadvertent second function in the conversion process (148). There is evidence for the participation of a speciesspecific macromolecule, posited to be a protein (designated 'protein X') (149)(150)(151).…”

Section: Lipid Rafts In Prion Diseasementioning

confidence: 99%

The role of lipid rafts in prion protein biology

Lewis

Hooper²

2011

Front Biosci

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The conformational conversion of the cellular prion protein, PrP(C), to the misfolded isoform PrP(Sc )is the central pathogenic event in the uniquely transmissible neurodegenerative prion diseases. As both PrP(C) and PrP(Sc) are associated with membranes, the nature of the membrane microenvironment may well play a significant role in both the conformational conversion process as well as the normal functions of PrP(C). Within the membrane are various microdomains, areas of distinct lipid and protein composition, the best studied of which are the cholesterol- and sphingolipid-rich lipid rafts. These domains are characterized biochemically by their relative resistance to solubilization in certain detergents at low temperature. In this article we review the evidence for the involvement of lipid rafts in the localization and trafficking of PrP(C), in the cellular signaling, neuroprotective and metal binding functions of PrP(C), and as sites for the conversion of PrP(C) to PrP(Sc) and in cell-to-cell prion transmission.

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Section: Lipid Rafts In Prion Diseasementioning

confidence: 99%

The role of lipid rafts in prion protein biology

Lewis

Hooper²

2011

Front Biosci

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“…The remarkable peculiarity of PrP to adopt several structurally favourable states requires a detailed contemplation of distinct structural parts of PrP C and their possible role in PrP C -PrP Sc interaction, misfolding and disease transmission. Cofactors, like metal ions [24, 25] or proteins [26, 27], are also thought to be involved in the structural determination of PrP, but the manner in which they influence structure and interaction with other molecules is yet to be determined. Furthermore, whether they have an effect in preventing prion protein misfolding is also in question.…”

Section: Introductionmentioning

confidence: 99%

Prion Protein Misfolding

Kupfer

Hinrichs²,

Groschup³

2009

CMM

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The crucial event in the development of transmissible spongiform encephalopathies (TSEs) is the conformational change of a host-encoded membrane protein - the cellular PrPC - into a disease associated, fibril-forming isoform PrPSc. This conformational transition from the α-helix-rich cellular form into the mainly β-sheet containing counterpart initiates an ‘autocatalytic’ reaction which leads to the accumulation of amyloid fibrils in the central nervous system (CNS) and to neurodegeneration, a hallmark of TSEs.The exact molecular mechanisms which lead to the conformational change are still unknown. It also remains to be brought to light how a polypeptide chain can adopt at least two stable conformations. This review focuses on structural aspects of the prion protein with regard to protein-protein interactions and the initiation of prion protein misfolding. It therefore highlights parts of the protein which might play a notable role in the conformational transition from PrPC to PrPSc and consequently in inducing a fatal chain reaction of protein misfolding. Furthermore, features of different proteins, which are able to adopt insoluble fibrillar states under certain circumstances, are compared to PrP in an attempt to understand the unique characteristics of prion diseases.

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“…The conformational change in β-sheet confers protein kinase resistance which leads in the end to neuronal loss and gliosis. Some suggest the involvement of an unknown protein called "protein X", a supposed chaperon protein as enhancer of endoproteolytic cleavage of PrP C to PrP Sc (9). Similarities to this kind of conformational change were observed at α-synuclein which is found in Parkinson's disease.…”

Section: Discussionmentioning

confidence: 94%