1. Both N-Terminal and C-Terminal Histidine Residues of the Prion Protein Are Essential for Copper Coordination and Neuroprotective Self-Regulation
- Author
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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, and Millhauser, Glenn L
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Brain Disorders ,Rare Diseases ,Neurodegenerative ,Emerging Infectious Diseases ,Transmissible Spongiform Encephalopathy (TSE) ,Neurosciences ,Infectious Diseases ,2.1 Biological and endogenous factors ,Neurological ,Animals ,Copper ,DNA Repeat Expansion ,Histidine ,Mice ,Models ,Molecular ,Molecular Dynamics Simulation ,Mutation ,Prion Proteins ,Protein Conformation ,Protein Domains ,Protein Folding ,PrP ,PrPC ,A beta 42 ,NMR ,EPR ,Aβ42 ,Medicinal and Biomolecular Chemistry ,Microbiology ,Biochemistry & Molecular Biology ,Biochemistry and cell biology - 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. more...
- Published
- 2020