Cellular prion protein acquires resistance to proteolytic degradation following copper ion binding.

Abstract:

:The conversion of cellular prion protein (PrP(C)) into its pathological isoform (PrP(Sc)) conveys an increase in hydrophobicity and induces a partial resistance to proteinase K (PK). Interestingly, co-incubation with high copper ion concentrations also modifies the solubility of PrP(c) and induces a partial PK resistance which was reminiscent of PrP(Sc). However, concerns were raised whether this effect was not due to a copper-induced inhibition of the PK itself. We have therefore analyzed the kinetics of the formation of PK-resistant PrP(C) and excluded possible interference effects by removing unbound copper ions prior to the addition of PK by methanol precipitation or immobilization of PrP(C) followed by washing steps. We found that preincubation of PrPc with copper ions at concentrations as low as 50 microM indeed rendered these proteins completely PK resistant, while control substrates were proteolyzed. No other divalent cations induced a similar effect. However, in addition to this specific stabilizing effect on PrP(C), higher copper ion concentrations in solution (>200 microM) directly blocked the enzymatic activity of PK, possibly by replacing the Ca2+ ions in the active center of the enzyme. Therefore, as a result of this inhibition the proteolytic degradation of PrP(C) as well as PrP(Sc) molecules was suppressed.

journal_name

Biol Chem

journal_title

Biological chemistry

authors

Kuczius T,Buschmann A,Zhang W,Karch H,Becker K,Peters G,Groschup MH

doi

10.1515/BC.2004.090

keywords:

subject

Has Abstract

pub_date

2004-08-01 00:00:00

pages

739-47

issue

8

eissn

1431-6730

issn

1437-4315

journal_volume

385

pub_type

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