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.

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

“…The regulation of prion functionality and conversion into toxic aggregates may be fundamentally propelled by LLPS [ 120 , 121 , 122 , 123 ], and the intrinsically disordered N-terminal region of the physiological PrP C has been shown to be necessary and sufficient for LLPS of PrP [ 266 , 267 ]. Large nucleation barriers enable deep supersaturation that favors the formation of toxic aggregates in Sup PrD while kinetic barriers for the formation of dynamic intracellular condensates are easily breached by PTMs and changes in salt, pH, and temperature during LLPS [ 251 , 268 , 269 ].…”

“…The unstructured N-terminal domain between residues 23 and 120 contains an octapeptide repeat region (residues 51–90) and an amyloidogenic region between residues 90 and 120 involving histidines 96 and 111, which bind metals with a special high affinity for copper [ 272 , 294 , 367 , 412 , 512 ], while residues 23–90 of the unstructured N-terminal constitute a region that specifically targets to lipid rafts, and PrP with deleted N-terminal is unable to bind to lipid rafts [ 325 ]. The constitutive, tight association between PrP C and lipid rafts [ 326 , 513 ] and its wide expression in stem cells [ 8 , 514 , 515 , 516 , 517 ] offer additional insight as to how prions interact with membrane supramolecular complexes [ 518 ] to participate in an extensive range of physiological functions including transcription, scaffolding, and signaling [ 267 ], and modulate cancer stemness, differentiation, self-renewal, and proliferation to augment cancer MDR [ 65 , 71 , 77 , 516 , 519 , 520 ]. Although PrP C does not bind iron directly, the binding of Cu 2+ in the N-terminal domain modulates iron metabolism through copper homeostasis [ 289 ].…”