The PrP-Like Proteins Shadoo and Doppel

Westaway, David; Daude, Nathalie; Wohlgemuth, Serene; Harrison, Paul M.

doi:10.1007/128_2011_190

Cited by 29 publications

(32 citation statements)

References 147 publications

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“…In this model, a subsequent gene duplication event, in addition to some form of genomic rearrangement, led to modern-day SPRN , which is situated on chromosome 10 in the human genome. A later, local duplication would have then given rise to modern-day PRNP and PRND , which are directly adjacent to one another in the genome (Westaway et al, 2011). Figure 1B displays an alternative scenario also outlined by Schmitt-Ulms et al (2009) but incorporating earlier research suggesting that SPRN may be evolutionarily more ancient than PRNP (Premzl et al, 2004).…”

Section: The Cellular Prion Protein and Its Genementioning

confidence: 99%

Physiological Functions of the Cellular Prion Protein

Castle

Gill

2017

Front. Mol. Biosci.

163

157

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The prion protein, PrPC, is a small, cell-surface glycoprotein notable primarily for its critical role in pathogenesis of the neurodegenerative disorders known as prion diseases. A hallmark of prion diseases is the conversion of PrPC into an abnormally folded isoform, which provides a template for further pathogenic conversion of PrPC, allowing disease to spread from cell to cell and, in some circumstances, to transfer to a new host. In addition to the putative neurotoxicity caused by the misfolded form(s), loss of normal PrPC function could be an integral part of the neurodegenerative processes and, consequently, significant research efforts have been directed toward determining the physiological functions of PrPC. In this review, we first summarise important aspects of the biochemistry of PrPC before moving on to address the current understanding of the various proposed functions of the protein, including details of the underlying molecular mechanisms potentially involved in these functions. Over years of study, PrPC has been associated with a wide array of different cellular processes and many interacting partners have been suggested. However, recent studies have cast doubt on the previously well-established links between PrPC and processes such as stress-protection, copper homeostasis and neuronal excitability. Instead, the functions best-supported by the current literature include regulation of myelin maintenance and of processes linked to cellular differentiation, including proliferation, adhesion, and control of cell morphology. Intriguing connections have also been made between PrPC and the modulation of circadian rhythm, glucose homeostasis, immune function and cellular iron uptake, all of which warrant further investigation.

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Section: The Cellular Prion Protein and Its Genementioning

confidence: 99%

Physiological Functions of the Cellular Prion Protein

Castle

Gill

2017

Front. Mol. Biosci.

163

157

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“…The hydrophobic domains, the part of PrP C and Sho that share more extended sequence similarity, have considerable influence on the toxic/protective phenotypes of PrP C 32 and Sho33. To assess its role in the drug hypersensitising phenotypes conferred by Sho expression, we deleted Sho’s HD (amino acid residues 62 through 77; ShoΔHD, Fig.…”

Section: Resultsmentioning

confidence: 99%

The prion protein family member Shadoo induces spontaneous ionic currents in cultured cells

Nyeste

Stincardini

Bencsura

et al. 2016

Sci Rep

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Some mutant forms of the cellular prion protein (PrPC) carrying artificial deletions or point mutations associated with familial human prion diseases are capable of inducing spontaneous ionic currents across the cell membrane, conferring hypersensitivity to certain antibiotics to a wide range of cultured cells and primary cerebellar granular neurons (CGNs). These effects are abrogated when the wild type (WT) form is co-expressed, suggesting that they might be related to a physiological activity of PrPC. Interestingly, the prion protein family member Shadoo (Sho) makes cells hypersensitive to the same antibiotics as mutant PrP-s, an effect that is diminished by the co-expression of WT-PrP. Here, we report that Sho engages in another mutant PrP-like activity: it spontaneously induces large ionic currents in cultured SH-SY5Y cells, as detected by whole-cell patch clamping. These currents are also decreased by the co-expression of WT-PrP. Furthermore, deletion of the N-terminal (RXXX)8 motif of Sho, mutation of the eight arginine residues of this motif to glutamines, or replacement of the hydrophobic domain by that of PrP, also diminish Sho-induced ionic currents. Our results suggest that the channel activity that is also characteristic to some pathogenic PrP mutants may be linked to a physiological function of Sho.

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“…PrP and Doppel are both involved in cell differentiation, but PrP in neurogenesis and Doppel in gametogenesis (Westaway, Daude, Wohlgemuth, & Harrison, 2011). Considering the broader function for PrP compared to Doppel's more specific function, Doppel may perform a subset of the original PrP function or a slightly modified function.…”

Section: Discussionmentioning

confidence: 99%

Did the prion protein become vulnerable to misfolding after an evolutionary divide and conquer event?

Richmond

Masterson

Ortíz

et al. 2013

Journal of Biomolecular Structure and Dynamics

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Despite high sequence identity among mammalian prion proteins, mammals have varying rates of susceptibility to prion disease resulting in a so-called species barrier. The species barrier follows no clear pattern, with closely related species or similar sequences being no more likely to infect each other, and remains an unresolved enigma. Variation of the conformationally flexible regions may alter the thermodynamics of the conformational change, commonly referred to as the conformational conversion, that occurs in the pathogenic process of the mammalian prion protein. A conformational ensemble scenario is supported by the species barrier in prion disease and evidence that there are strains of pathogenic prion with different conformations within species. To study how conformational flexibility has evolved in the prion protein, an investigation was undertaken of the evolutionary dynamics of structurally disordered regions in the mammalian prion protein, non-mammalian prion protein that is not vulnerable to prion disease, and remote homologs Doppel and Shadoo. Structural disorder prediction analyzed in an evolutionary context revealed that the occurrence of increased or altered conformational flexibility in mammalian prion proteins coincides with key events among PrP, Doppel, and Shadoo. Comparatively rapid evolutionary dynamics of conformational flexibility in the prion protein suggest that the species barrier is not a static phenomenon. A small number of amino acid substitutions can repopulate the conformational ensemble and have a disproportionately large effect on pathogenesis.

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The PrP-Like Proteins Shadoo and Doppel

Cited by 29 publications

References 147 publications

Physiological Functions of the Cellular Prion Protein

Physiological Functions of the Cellular Prion Protein

The prion protein family member Shadoo induces spontaneous ionic currents in cultured cells

Did the prion protein become vulnerable to misfolding after an evolutionary divide and conquer event?

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