Biological Functions of the Intrinsically Disordered N-Terminal Domain of the Prion Protein: A Possible Role of Liquid-Liquid Phase Separation

Biomolecules. 2021 Aug 12;11(8):1201. doi: 10.3390/biom11081201.


The mammalian prion protein (PrPC) is composed of a large intrinsically disordered N-terminal and a structured C-terminal domain, containing three alpha-helical regions and a short, two-stranded beta-sheet. Traditionally, the activity of a protein was linked to the ability of the polypeptide chain to adopt a stable secondary/tertiary structure. This concept has been extended when it became evident that intrinsically disordered domains (IDDs) can participate in a broad range of defined physiological activities and play a major functional role in several protein classes including transcription factors, scaffold proteins, and signaling molecules. This ability of IDDs to engage in a variety of supramolecular complexes may explain the large number of PrPC-interacting proteins described. Here, we summarize diverse physiological and pathophysiological activities that have been described for the unstructured N-terminal domain of PrPC. In particular, we focus on subdomains that have been conserved in evolution.

Keywords: intrinsically disordered; liquid–liquid phase separation; neurodegeneration; prion; stress protection.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Humans
  • Liquid-Liquid Extraction / methods*
  • Prion Proteins / analysis
  • Prion Proteins / genetics*
  • Prion Proteins / metabolism*
  • Protein Domains / physiology


  • Prion Proteins