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), S. 4408-4425
Online
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Zugriff:
The cellular prion protein (PrP(C)) is comprised of two domains – a globular C-terminal domain and an unstructured N-terminal domain. Recently, copper has been observed to drive tertiary contact in PrP(C), 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 PrP(C) 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 Cu(2+) 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 PrP(C)’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: | M. Jake Pushie ; Millhauser, Glenn L. ; Harris, David A. ; Ubilla-Rodriguez, Natalia C. ; R. David Britt ; Kiblen, Joseph T. M. ; Schilling, Kevin M. ; Wu, Bei ; Roseman, Graham ; Tao, Lizhi |
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Zeitschrift: | Journal of Molecular Biology, Jg. 432 (2020-07-01), S. 4408-4425 |
Veröffentlichung: | Elsevier BV, 2020 |
Medientyp: | unknown |
ISSN: | 0022-2836 (print) |
DOI: | 10.1016/j.jmb.2020.05.020 |
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