Disordered structure and flexible roles: using the prion protein N1 fragment for neuroprotective and regenerative therapy

摘要

Thecellular prion protein (PrPC) isatruly remarkablecellsurface glycoprotein. With (i) its broad expression pattern and (ii) particularly high levelsin the nervous system, (iii) itscriticalinvolvement in fatal neurodegenerative diseasesaffecting differentmammalian species, (iv) its structurallydiverging bipartite buildup, (v) its high degree ofevolutionary conservation and (vi)a variety of –at leastsuggested– functions despite(vii)asurprising lack ofmajor phenotypic deficits when absent (as in respective knock-outanimals), PrPC has raised considerableresearch interest overthelast four decades. While most oftheseaspects have been reviewed extensively in the past (Linsenmeieretal., 2017), this perspective willfocusexclusively on asoluble peptide, termed N1, which isconstitutively generated by the main proteolyticcleavageevent occurring on PrPC [Figure1]B. In fact,considering that particular fragments ofPrPC account for intrinsicfunctions, may help to explain the multitude of physiologicalroles sofar mostly –and maybein partmistakenly– attributed to full-length PrPC as the‘precursor’. The N1 fragment basically consists oftheflexible Nterminal half ofPrPC (after removal ofthesignal peptide) ranging fromresidue 23 to ~110,contains severalsites forcoordinative binding ofdivalentcationsand interactionwith other binding partners,and representsa primeexample ofan intrinsically disordered peptide(Gonsberg etal.,2017). Physiologically it results fromthe α-cleavage ofPrPC whichmay take placeat oren routeto thecellsurface orafter re-internalization inendosomalcompartments.