Both N-Terminal and C-Terminal Histidine Residues of the Prion Protein Are Essential for Copper Coordination and Neuroprotective Self-Regulation
In: Journal of Molecular Biology, Jg. 432 (2020-07-01), Heft 16
Online
academicJournal
- 4408 - 4425
The cellular prion protein (PrPC) comprises two domains: a globular C-terminal domain and an unstructured N-terminal domain. Recently, copper has been observed to drive tertiary contact in PrPC, inducing a neuroprotective cis interaction that structurally links the protein's two domains. The location of this interaction on the C terminus overlaps with the sites of human pathogenic mutations and toxic antibody docking. Combined with recent evidence that the N terminus is a toxic effector regulated by the C terminus, there is an emerging consensus that this cis interaction serves a protective role, and that the disruption of this interaction by misfolded PrP oligomers may be a cause of toxicity in prion disease. We demonstrate here that two highly conserved histidines in the C-terminal domain of PrPC are essential for the protein's cis interaction, which helps to protect against neurotoxicity carried out by its N terminus. We show that simultaneous mutation of these histidines drastically weakens the cis interaction and enhances spontaneous cationic currents in cultured cells, the first C-terminal mutant to do so. Whereas previous studies suggested that Cu2+ coordination was localized solely to the protein's N-terminal domain, we find that both domains contribute equatorially coordinated histidine residue side-chains, resulting in a novel bridging interaction. We also find that extra N-terminal histidines in pathological familial mutations involving octarepeat expansions inhibit this interaction by sequestering copper from the C terminus. Our findings further establish a structural basis for PrPC's C-terminal regulation of its otherwise toxic N terminus.
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Both N-Terminal and C-Terminal Histidine Residues of the Prion Protein Are Essential for Copper Coordination and Neuroprotective Self-Regulation
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Autor/in / Beteiligte Person: | Schilling, Kevin M ; Tao, Lizhi ; Wu, Bei ; Kiblen, Joseph TM ; Ubilla-Rodriguez, Natalia C ; Pushie, M Jake ; Britt, R David ; Roseman, Graham P ; Harris, David A ; Millhauser, Glenn L |
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Zeitschrift: | Journal of Molecular Biology, Jg. 432 (2020-07-01), Heft 16 |
Veröffentlichung: | eScholarship, University of California, 2020 |
Medientyp: | academicJournal |
Umfang: | 4408 - 4425 |
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