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  Molecular Features of the Copper Binding Sites in the Octarepeat Domain of the Prion Protein†

Burns, C., Aronoff-Spencer, E., Dunham, C., Lario, P., Avdievich, N., Antholine, W., et al. (2002). Molecular Features of the Copper Binding Sites in the Octarepeat Domain of the Prion Protein†. Biochemistry, 41(12), 3991-4001. doi:10.1021/bi011922x.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-850F-5 Version Permalink: http://hdl.handle.net/21.11116/0000-0005-8510-2
Genre: Journal Article

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https://pubs.acs.org/doi/pdf/10.1021/bi011922x (Publisher version)
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 Creators:
Burns, CS, Author
Aronoff-Spencer, E, Author
Dunham, CM, Author
Lario, P, Author
Avdievich, NI1, Author              
Antholine, WE, Author
Olmstead, MM, Author
Vrielink, A, Author
Gerfen, GJ, Author
Peisach , J, Author
Scott, WG, Author
Millhauser, GL, Author
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1External Organizations, ou_persistent22              

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 Abstract: Recent evidence suggests that the prion protein (PrP) is a copper binding protein. The N-terminal region of human PrP contains four sequential copies of the highly conserved octarepeat sequence PHGGGWGQ spanning residues 60−91. This region selectively binds Cu2+ in vivo. In a previous study using peptide design, EPR, and CD spectroscopy, we showed that the HGGGW segment within each octarepeat comprises the fundamental Cu2+ binding unit [Aronoff-Spencer et al. (2000) Biochemistry40, 13760−13771]. Here we present the first atomic resolution view of the copper binding site within an octarepeat. The crystal structure of HGGGW in a complex with Cu2+ reveals equatorial coordination by the histidine imidazole, two deprotonated glycine amides, and a glycine carbonyl, along with an axial water bridging to the Trp indole. Companion S-band EPR, X-band ESEEM, and HYSCORE experiments performed on a library of 15N-labeled peptides indicate that the structure of the copper binding site in HGGGW and PHGGGWGQ in solution is consistent with that of the crystal structure. Moreover, EPR performed on PrP(23−28, 57−91) and an 15N-labeled analogue demonstrates that the identified structure is maintained in the full PrP octarepeat domain. It has been shown that copper stimulates PrP endocytosis. The identified Gly−Cu linkage is unstable below pH ≈6.5 and thus suggests a pH-dependent molecular mechanism by which PrP detects Cu2+ in the extracellular matrix or releases PrP-bound Cu2+ within the endosome. The structure also reveals an unusual complementary interaction between copper-structured HGGGW units that may facilitate molecular recognition between prion proteins, thereby suggesting a mechanism for transmembrane signaling and perhaps conversion to the pathogenic form.

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 Dates: 2002-03
 Publication Status: Published in print
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 Identifiers: DOI: 10.1021/bi011922x
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Title: Biochemistry
Source Genre: Journal
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Publ. Info: Columbus, Ohio : American Chemical Society
Pages: - Volume / Issue: 41 (12) Sequence Number: - Start / End Page: 3991 - 4001 Identifier: ISSN: 0006-2960
CoNE: https://pure.mpg.de/cone/journals/resource/954925384103