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Cited by 417

The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.

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

Open access
Burns, Colin S., Aronoff-Spencer, Eliah, Dunham, Christine M., Lario, Paula, Avdievich, Nikolai I., Antholine, William E., Olmstead, Marilyn M., Vrielink, Alice, Gerfen, Gary J., Peisach, Jack, Scott, William G., Millhauser, Glenn L.·2002·Biochemistry
DOI 10.1021/bi011922x
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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) Biochemistry 40, 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 approximately 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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Metadata

Authors
Burns, C. S., Aronoff-Spencer, E., Dunham, C. M., Lario, P., Avdievich, N. I., Antholine, W. E., Olmstead, M. M., Vrielink, A., Gerfen, G. J., Peisach, J., Scott, W. G., & Millhauser, G. L.
Venue
Biochemistry
Publisher
American Chemical Society (ACS)
Published
2002-03-01
Volume
41
Issue
12
Pages
3991-4001
ISSN
  • 0006-2960 (ISSN-L)
  • 1520-4995
DOI
10.1021/bi011922x
OpenAlex
W2157784883
Cited by
417
References
38
FWCI
9.07
Type
journal article
Language
en
Open access
green

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