Scavenger, transducer, RNA chaperone? What ligands of the prion protein teach us about its function

Marc, Daniel; Mercey, R.; Lantier, Frédéric

doi:10.1007/s00018-007-6370-1

Cited by 19 publications

(15 citation statements)

References 176 publications

(239 reference statements)

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“…This is at variance with most of the PrP ligands (DNA, RNA, heparin, etc. ), which have been described to interact with the PrP N terminus (33). On the contrary, some quinacrine derivatives showing antiprion activity bind the C terminus of H3 (34, 35) but how this interaction is related to structural conversion is not known.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic insights into cellular alteration of prion by poly‐D‐lysine: the role of H2H3 domain

Xu¹,

Adrover

Pastore

et al. 2011

FASEB j.

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Misfolding of the prion protein (PrP) is the central feature of prion diseases. The conversion of the normal α-helical PrP(C) into a pathological β-enriched PrP(Sc) constitutes an early event in the infectious process. Several hypotheses, involving different regions of the protein, endeavor to delineate the structural mechanism underlying this change of conformation. All current working hypotheses, however, are based on biophysical and modeling studies, the biological relevance of which still needs to be assessed. We have studied the effect of positively charged polymers on the conversion, using polylysine as a model system, and have investigated a possible mechanism of structural stabilization. We have shown that poly-D-lysine removes proteinase K-resistant PrP from prion-infected SN56 neuroblastoma cells without affecting PrP(C). The effect is enantiospecific since the levorotary isomer, poly-L-lysine, has a markedly weaker effect, likely because of its higher susceptibility to degradation. In vitro cross-linking and NMR studies confirm a direct interaction between polylysine and PrP, which mainly maps to the PrP region containing helices 2 and 3 (H2H3). Interaction prevents conformational conversion and protein aggregation. Our results establish a central role of H2H3 in PrP(Sc) amyloidogenesis and replication and provide biological relevance for the pathological misfolding of this domain.

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Section: Discussionmentioning

confidence: 99%

Mechanistic insights into cellular alteration of prion by poly‐D‐lysine: the role of H2H3 domain

Xu¹,

Adrover

Pastore

et al. 2011

FASEB j.

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“…The C-terminal portion of PrP is mostly α-helical in PrP C and changes to all β-sheet in PrP Sc . The physiological function(s) of PrP remains unknown, although roles have been proposed in antiapoptosis; antioxidation; sensing and transport of copper or other metals; neuronal development, differentiation, and maintenance; and even in the immune system (Marc et al , 2007). The proposed functions are based on interactions between PrP and metals, other proteins, or nucleic acids.…”

Section: Prolyl 4-hydroxylasementioning

confidence: 99%

Prolyl 4-hydroxylase

Gorres

Raines

2010

Critical Reviews in Biochemistry and Molecular Biology

528

591

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Posttranslational modifications can cause profound changes in protein function. Typically, these modifications are reversible, and thus provide a biochemical on–off switch. In contrast, proline residues are the substrates for an irreversible reaction that is the most common posttranslational modification in humans. This reaction, which is catalyzed by prolyl 4-hydroxylase (P4H), yields (2S,4R)-4-hydroxyproline (Hyp). The protein substrates for P4Hs are diverse. Likewise, the biological consequences of prolyl hydroxylation vary widely, and include altering protein conformation and protein–protein interactions, and enabling further modification. The best known role for Hyp is in stabilizing the collagen triple helix. Hyp is also found in proteins with collagen-like domains, as well as elastin, conotoxins, and argonaute 2. A prolyl hydroxylase domain protein acts on the hypoxia inducible factor α, which plays a key role in sensing molecular oxygen, and could act on inhibitory κB kinase and RNA polymerase II. P4Hs are not unique to animals, being found in plants and microbes as well. Here, we review the enzymic catalysts of prolyl hydroxylation, along with the chemical and biochemical consequences of this subtle but abundant posttranslational modification.

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“…This absence of infectivity in sheep semen may reflect the lack of transconformation of the prion protein in the genital tract due to either the specific biochemical properties of the different glycosylated and truncated forms present (Shaked et al 1999, Ecroyd et al 2005 or the high level of protection formed by the testicular and epididymal blood barrier (Cyr et al 2007). It could also be hypothesized that these tissues lack one or more (still unidentified) cofactors needed for the efficient conversion of PrP C to PrP Sc (Telling et al 1995, Marc et al 2007.…”

Section: Prpmentioning

confidence: 99%

Semen from scrapie-infected rams does not transmit prion infection to transgenic mice

Sarradin¹,

Melo²,

Barc³

et al. 2008

Reproduction

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Scrapie is the most common transmissible spongiform encephalopathy (TSE) in livestock. Natural contamination in sheep flocks is presumed to occur by maternal transmission to offspring. However, horizontal prion transmission from animal to animal exists and may be significant in sustaining and spreading contagion in the field. Artificial insemination is widely used in modern farming, and as large amounts of prion protein have been found in sheep sperm membrane, epididymal fluid and seminal plasma, horizontal transmission by this route was hypothesized since no clear information has been obtained on possible sexual transmission of TSE. We therefore tested the contamination levels of semen from scrapie-infected rams at different stages of incubation, including the clinical phase of the disease. We report here that under our experimental conditions ram semen did not transmit infectivity to scrapie-susceptible transgenic mice overexpressing the V 136 R 154 Q 171 allele of the sheep prion (PRNP) gene.These results suggest that artificial insemination and natural mating have a very low or negligible potential for the transmission of scrapie in sheep flocks.Reproduction (2008) 135 415-418

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Scavenger, transducer, RNA chaperone? What ligands of the prion protein teach us about its function

Cited by 19 publications

References 176 publications

Mechanistic insights into cellular alteration of prion by poly‐D‐lysine: the role of H2H3 domain

Mechanistic insights into cellular alteration of prion by poly‐D‐lysine: the role of H2H3 domain

Prolyl 4-hydroxylase

Semen from scrapie-infected rams does not transmit prion infection to transgenic mice

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