Probing the N‑Terminal β‑Sheet Conversion in the Crystal Structure of the Human Prion Protein Bound to a Nanobody

Prions are fatal neurodegenerative
transmissible agents causing
several incurable illnesses in humans and animals. Prion diseases
are caused by the structural conversion of the cellular prion protein,
PrPC, into its misfolded oligomeric form, known as prion
or PrPSc. The canonical human PrPC (HuPrP) fold
features an unstructured N-terminal part (residues 23–124)
and a well-defined C-terminal globular domain (residues 125–231).
Compelling evidence indicates that an evolutionary N-terminal conserved
motif AGAAAAGA (residues 113–120) plays an important role in
the conversion to PrPSc. The intrinsic flexibility of the
N-terminal has hampered efforts to obtain detailed atomic information
on the structural features of this palindromic region. In this study,
we crystallized the full-length HuPrP in complex with a nanobody (Nb484)
that inhibits prion propagation. In the complex, the prion protein
is unstructured from residue 23 to 116. The palindromic motif adopts
a stable and fully extended configuration to form a three-stranded
antiparallel β-sheet with the β1 and β2 strands,
demonstrating that the full-length HuPrPC can adopt a more
elaborate β0-β1-α1-β2-α2-α3 structural
organization than the canonical β1-α1-β2-α2-α3
prion-like fold. From this structure, it appears that the palindromic
motif mediates β-enrichment in the PrPC monomer as
one of the early events in the conversion of PrPC into
PrPSc.