The N-terminus of the prion protein is a toxic effector regulated by the C-terminus

Wu, Bei; McDonald, Alex J.; Markham, Kathleen; Rich, Celeste B.; McHugh, Kyle P.; Tatzelt, Jörg; Colby, David W.; Millhauser, Glenn L. und Harris, David A. (2017): The N-terminus of the prion protein is a toxic effector regulated by the C-terminus. In: Elife, Bd. 6, e23473

Abstract

PrPc, the cellular isoform of the prion protein, serves to transduce the neurotoxic effects of PrPSc, the infectious isoform, but how this occurs is mysterious. Here, using a combination of electrophysiological, cellular, and biophysical techniques, we show that the flexible, N-terminal domain of PrPc functions as a powerful toxicity-transducing effector whose activity is tightly regulated in cis by the globular C-terminal domain. Ligands binding to the N-terminal domain abolish the spontaneous ionic currents associated with neurotoxic mutants of PrP, and the isolated N-terminal domain induces currents when expressed in the absence of the C-terminal domain. Anti-PrP antibodies targeting epitopes in the C-terminal domain induce currents, and cause degeneration of dendrites on murine hippocampal neurons, effects that entirely dependent on the effector function of the N-terminus. NMR experiments demonstrate intramolecular docking between N- and C-terminal domains of PrPc, revealing a novel auto-inhibitory mechanism that regulates the functional activity of PrPc.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2050-084X
• Sprache: Englisch