| First Author | Wu B | Year | 2017 |
| Journal | Elife | Volume | 6 |
| PubMed ID | 28527237 | Mgi Jnum | J:259251 |
| Mgi Id | MGI:6116909 | Doi | 10.7554/eLife.23473 |
| Citation | Wu B, et al. (2017) The N-terminus of the prion protein is a toxic effector regulated by the C-terminus. Elife 6:e23473 |
| abstractText | PrP(C), the cellular isoform of the prion protein, serves to transduce the neurotoxic effects of PrP(Sc), 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 PrP(C) 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 PrP(C), revealing a novel auto-inhibitory mechanism that regulates the functional activity of PrP(C). |
