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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.

Abstract：

: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.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Schilling KM,Tao L,Wu B,Kiblen JTM,Ubilla-Rodriguez NC,Pushie MJ,Britt RD,Roseman GP,Harris DA,Millhauser GL

doi

10.1016/j.jmb.2020.05.020

subject

Has Abstract

pub_date

2020-07-24 00:00:00

pages

4408-4425

issue

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(20)30369-7

journal_volume

432

pub_type

杂志文章

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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.