Copper Reduction by the Octapeptide Repeat Region of Prion Protein: pH Dependence and Implications in Cellular Copper Uptake
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- 作者：Takashi Miura ; Satoshi Sasaki ; Akira Toyama ; and Hideo Takeuchi
- 刊名：Biochemistry
- 出版年：2005
- 出版时间：June 21, 2005
- 年：2005
- 卷：44
- 期：24
- 页码：8712 - 8720
- 全文大小：168K
- 年卷期：v.44,no.24(June 21, 2005)
- ISSN：1520-4995
文摘
The physiological function of the prion protein (PrP) remains enigmatic despite its establishedinvolvement in the pathogenesis of spongiform encephalopathies. PrP is a glycolipid-anchored membraneprotein, which constitutively recycles between the cell surface and an endosomal compartment. TheN-terminal region of PrP contains a four tandem repeat (OP4) of the octapeptide PHGGGWGQ (OP) thatbinds and reduces Cu(II) ions. We have examined the kinetic properties of the OP4-mediated Cu(II)reduction and found that OP4 exhibits the highest reduction activity around pH 6.5, close to the pH inearly endosomes. All four OP units and at least one tryptophan side chain are essential for Cu(II) reduction.The reaction is described by an uncompetitive substrate inhibition mechanism involving a 1:1 Cu(II)-OP4 active intermediate. Structural analysis by Raman spectroscopy has revealed that the Cu(II) ion iscoordinated by four histidine N
atoms in the active intermediate and the feasibility of formation of thisintermediate correlates with the Cu(II) reduction over a pH range from 5.0 to 8.2. Molecular mechanicscalculations suggest that two tryptophan residues of OP4 are located near the Cu(II) site, being consistentwith the importance of redox-active tryptophan in the Cu(II) reduction. PrP has been proposed to captureCu(II) ions in the extracellular space and release them in the endosome. The results of this study stronglysuggest that PrP also plays a role in the reduction of captured Cu(II) ions prior to their transfer to Cu(I)-specific intracellular copper trafficking proteins.
atoms in the active intermediate and the feasibility of formation of thisintermediate correlates with the Cu(II) reduction over a pH range from 5.0 to 8.2. Molecular mechanicscalculations suggest that two tryptophan residues of OP4 are located near the Cu(II) site, being consistentwith the importance of redox-active tryptophan in the Cu(II) reduction. PrP has been proposed to captureCu(II) ions in the extracellular space and release them in the endosome. The results of this study stronglysuggest that PrP also plays a role in the reduction of captured Cu(II) ions prior to their transfer to Cu(I)-specific intracellular copper trafficking proteins.