The most common form of prion disease in humans is sCJD (sporadic Creutzfeldt–Jakob disease). The naturally occurring E219K polymorphism in the HuPrP (human prion protein) is considered to protect against sCJD. To gain insight into the structural basis of its protective influence we have determined the NMR structure of recombinant HuPrP (residues 90–231) carrying the E219K polymorphism. The structure of the HuPrP(E219K) protein consists of a disordered N-terminal tail (residues 90–124) and a well-structured C-terminal segment (residues 125–231) containing three α-helices and two short antiparallel β-strands. Comparison of NMR structures of the wild-type and HuPrPs with pathological mutations under identical experimental conditions revealed that, although the global architecture of the protein remains intact, replacement of Glu219 with a lysine residue introduces significant local structural changes. The structural findings of the present study suggest that the protective influence of the E219K polymorphism is due to the alteration of surface charge distribution, in addition to subtle structural rearrangements localized within the epitopes critical for prion conversion.

The cellular form of the prion protein (PrP^C) is a highly conserved glycoprotein mostly expressed in the central and peripheral nervous systems by different cell types in mammals. A misfolded, pathogenic isoform, denoted as prion, is related to a class of neurodegenerative diseases known as transmissible spongiform encephalopathy. PrP^C function has not been unequivocally clarified, and it is rather defined as a pleiotropic protein likely acting as a dynamic cell surface scaffolding protein for the assembly of different signaling modules. Among the variety of PrP^C protein interactors, the neuronal cell adhesion molecule (NCAM) has been studied in vivo, but the structural basis of this functional interaction is still a matter of debate. Here we focused on the structural determinants responsible for human PrP^C (HuPrP) and NCAM interaction using stimulated emission depletion (STED) nanoscopy, SPR, and NMR spectroscopy approaches. PrP^C co-localizes with NCAM in mouse hippocampal neurons, and this interaction is mainly mediated by the intrinsically disordered PrP^C N-terminal tail, which binds with high affinity to the NCAM fibronectin type-3 domain. NMR structural investigations revealed surface-interacting epitopes governing the interaction between HuPrP N terminus and the second module of the NCAM fibronectin type-3 domain. Our data provided molecular details about the interaction between HuPrP and the NCAM fibronectin domain, and revealed a new role of PrP^C N terminus as a dynamic and functional element responsible for protein-protein interaction.

The post-translational conversion of the ubiquitously expressed cellular form of the prion protein, PrP^C, into its misfolded and pathogenic isoform, known as prion or PrP^Sc, plays a key role in prion diseases. These maladies are denoted transmissible spongiform encephalopathies (TSEs) and affect both humans and animals. A prerequisite for understanding TSEs is unraveling the molecular mechanism leading to the conversion process whereby most α-helical motifs are replaced by β-sheet secondary structures. Importantly, most point mutations linked to inherited prion diseases are clustered in the C-terminal domain region of PrP^C and cause spontaneous conversion to PrP^Sc. Structural studies with PrP variants promise new clues regarding the proposed conversion mechanism and may help identify “hot spots” in PrP^C involved in the pathogenic conversion. These investigations may also shed light on the early structural rearrangements occurring in some PrP^C epitopes thought to be involved in modulating prion susceptibility. Here we present a detailed overview of our solution-state NMR studies on human prion protein carrying different pathological point mutations and the implications that such findings may have for the future of prion research.

The mechanical adaptability of a family of six one-dimensional crystalline coordination polymers (CPs) of cadmium ([CdX₂(3-X′py)₂]_n; 1: X = Br, X′ = Cl, 2: X = I, X′ = Cl, 3: X = I, X′ = Br, 4: X = Cl, X′ = I, 5: X = Br, X′ = I, and 6: X, X′ = I) to applied external force was examined, and a plethora of flexible responses was noticed. While two of the six CPs (4 and 6) were slightly elastic, the remaining four CPs (1–3 and 5) presented variable plastic deformation; three of these (1–3) displayed exceptional crystal flow, and one (2) demonstrated unprecedented ductility of crystalline metal–organic material. The feature was examined by theory and custom-designed experiments, and it was shown that specific and directional intermolecular interactions are not only the most influential structural feature in determining the type of mechanical responses (i.e., elastic vs plastic), with interlocking of adjacent molecules playing only a supportive role, but also an unavoidable tool for dialing-in a diversity of plastic responses in Cd(II) coordination polymers.