Normal prion protein has an activity like that of superoxide dismutase

Brown, David R.; Wong, Boon Seng; Hafiz, Farida; Clive, Christine; Haswell, Stephen J.; Jones, Ian M.

doi:10.1042/bj3440001

Cited by 374 publications

(151 citation statements)

References 28 publications

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“…Alternatively, PrP has been viewed as an antioxidant defense molecule. In this line, several reports have suggested that PrP, particularly if refolded in the presence of millimolar concentrations of Cu 2ϩ , has SOD activity (22,23). However, these findings remain controversial, because brains from PrP-deficient mice exhibit unchanged SOD activity (24).…”

Section: Discussionmentioning

confidence: 67%

Copper-catalyzed oxidation of the recombinant SHa(29–231) prion protein

Requena

Groth

Legname

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

144

115

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Metal-catalyzed oxidation may result in structural damage to proteins and has been implicated in aging and disease, including neurological disorders such as Alzheimer's disease and amyotrophic lateral sclerosis. The selective modification of specific amino acid residues with high metal ion affinity leads to subtle structural changes that are not easy to detect but may have dramatic consequences on physical and functional properties of the oxidized protein molecules. PrP contains a histidine-rich octarepeat domain that binds copper. Because copper-binding histidine residues are particularly prone to metal-catalyzed oxidation, we investigated the effect of this reaction on the recombinant prion protein SHaPrP(29 -231). Using Cu 2؉ ͞ascorbate, we oxidized SHaPrP(29 -231) in vitro. Oxidation was demonstrated by liquid chromatography͞mass spectrometry, which showed the appearance of protein species of higher mass, including increases in multiples of 16, characteristic of oxygen incorporation. Digestion studies using Lys C indicate that the 29 -101 region, which includes the histidinecontaining octarepeats, is particularly affected by oxidation. Oxidation was time-and copper concentration-dependent and was evident with copper concentrations as low as 1 M. Concomitant with oxidation, SHaPrP(29 -231) suffered aggregation and precipitation, which was nearly complete after 15 min, when the prion protein was incubated at 37°C with a 6-fold molar excess of Cu 2؉ . These findings indicate that PrP, a copper-binding protein, may be particularly susceptible to metal-catalyzed oxidation and that oxidation triggers an extensive structural transition leading to aggregation.

show abstract

Section: Discussionmentioning

confidence: 67%

Copper-catalyzed oxidation of the recombinant SHa(29–231) prion protein

Requena

Groth

Legname

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

144

115

View full text Add to dashboard Cite

show abstract

“…In addition, copper chelators can induce spongiform change in experimental animals (6) and it has been claimed that the levels of copper in the brains of PrP-null mice are lower than in wild-type mice, although this has not been replicated by other workers (7,8). Moreover, it has been reported that recombinant PrP possesses copper-dependent superoxide dismutase, albeit at low levels (9). The prion protein has also been proposed to function as a copper transport protein for internalization of copper(II) ions (10).…”

mentioning

confidence: 85%

Location and properties of metal-binding sites on the human prion protein

Jackson

Murray

Hosszu

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

462

533

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“…The N terminus of PrP contains octarepeat sequences (PHGGG-WGQ) that coordinate copper ions (11,12), and the binding of copper has been reported to stimulate endocytosis of PrP (13). PrP-deficient (Prnp 0/0 ) mice have been reported to have diminished levels of copper in their brains and altered levels of superoxide dismutase activity (14,15), but these findings could not be confirmed (16). Among other suggested functions for PrP C are roles in neuritogenesis (17) and cell adhesion (18).…”

mentioning

confidence: 99%