| First Author | Kamps J | Year | 2021 |
| Journal | J Biol Chem | Volume | 297 |
| Issue | 1 | Pages | 100860 |
| PubMed ID | 34102212 | Mgi Jnum | J:325958 |
| Mgi Id | MGI:6720113 | Doi | 10.1016/j.jbc.2021.100860 |
| Citation | Kamps J, et al. (2021) The N-terminal domain of the prion protein is required and sufficient for liquid-liquid phase separation: A crucial role of the Abeta-binding domain. J Biol Chem 297(1):100860 |
| abstractText | Formation of biomolecular condensates through liquid-liquid phase separation (LLPS) has been described for several pathogenic proteins linked to neurodegenerative diseases and is discussed as an early step in the formation of protein aggregates with neurotoxic properties. In prion diseases, neurodegeneration and formation of infectious prions is caused by aberrant folding of the cellular prion protein (PrP(C)). PrP(C) is characterized by a large intrinsically disordered N-terminal domain and a structured C-terminal globular domain. A significant fraction of mature PrP(C) is proteolytically processed in vivo into an entirely unstructured fragment, designated N1, and the corresponding C-terminal fragment C1 harboring the globular domain. Notably, N1 contains a polybasic motif that serves as a binding site for neurotoxic Abeta oligomers. PrP can undergo LLPS; however, nothing is known how phase separation of PrP is triggered on a molecular scale. Here, we show that the intrinsically disordered N1 domain is necessary and sufficient for LLPS of PrP. Similar to full-length PrP, the N1 fragment formed highly dynamic liquid-like droplets. Remarkably, a slightly shorter unstructured fragment, designated N2, which lacks the Abeta-binding domain and is generated under stress conditions, failed to form liquid-like droplets and instead formed amorphous assemblies of irregular structures. Through a mutational analysis, we identified three positively charged lysines in the postoctarepeat region as essential drivers of condensate formation, presumably largely via cation-pi interactions. These findings provide insights into the molecular basis of LLPS of the mammalian prion protein and reveal a crucial role of the Abeta-binding domain in this process. |
