Biological functions of the intrinsically disordered n‐terminal domain of the prion protein: A possible role of liquid–liquid phase separation

Abstract

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.