The Structure of Human Prions: From Biology to Structural Models—Considerations and Pitfalls

Abstract

Prion diseases are a family of transmissible, progressive, and uniformly fatal neurodegenerative disorders that affect humans and animals. Although cross-species transmissions of prions are usually limited by an apparent “species barrier”, the spread of a prion disease to humans by ingestion of contaminated food, or via other routes of exposure, indicates that animal prions can pose a significant public health risk. The infectious agent responsible for the transmission of prion diseases is a misfolded conformer of the prion protein, PrPSc, a pathogenic isoform of the host-encoded, cellular prion protein, PrPC. The detailed mechanisms of prion conversion and replication, as well as the high-resolution structure of PrPSc, are unknown. This review will discuss the general background related to prion biology and assess the structural models proposed to date, while highlighting the experimental challenges of elucidating the structure of PrPSc.

Techniques to elucidate the conformation of prions

“…A lot of structural models for PrP SC exist but as discussed recently by Requena and Wille "the results and/or their interpretation remain controversial" [61] . For a better understanding of the conversion of PrP …”

Prion protein—Semisynthetic prion protein (PrP) variants with posttranslational modifications

“…Current estimates for dissociation constant ( K d ) values vary betweeen the micromolar and femtomolar range . The central hydrophobic domain (HD), comprising of aas 113 to 135, serves as a transmembrane domain and includes a palindromic region (AGAAAAGA, aa 113‐120) thought to be important in the PrP C ‐PrP Sc conversion . Within the C ‐terminal region, three α‐helices (aa 144‐154, 175‐193, and 200‐219), with two of them connected by a disulfide bond, and a small antiparallel β‐sheet (aa 128‐131 and 161‐164) are present.…”

“…50 The central hydrophobic domain (HD), comprising of aas 113 to 135, serves as a transmembrane domain 33 and includes a palindromic region (AGAAAAGA, aa 113-120) thought to be important in the PrP C -PrP Sc conversion. 58,59 Within the C-terminal region, three α-helices (aa 144-154, 175-193, and 200-219), with two of them connected by a disulfide bond, 60 and a small antiparallel β-sheet (aa 128-131 and 161-164) are present. As posttranslational modifications (PTMs), a Cterminal GPI anchor linked to serine 231 and two N-linked glycosylation sites at asparagines 181 and 197 exist.…”

The protonation state of histidine 111 regulates the aggregation of the evolutionary most conserved region of the human prion protein

“…It is, therefore, of importance to gather insights into the structure of protein fibrils as found in neurodegenerative diseases. In particular, the profound change in secondary structure—from α‐helical to β‐sheet—and the concomitant aggregation of the prion protein (PrP) has been closely associated with transmissible spongiform encephalopathies . In humans, Creutzfeldt–Jakob disease and Gertsmann–Sträussler–Scheinker syndrome represent two of the most common manifestations of prion‐related pathologies .…”

“…In particular, the profound change in secondary structure-from a-helical to b-sheet-and the concomitant aggregation of the prion protein (PrP) has been closely associated with transmissible spongiform encephalopathies. [7][8][9] In humans, Creutzfeldt-Jakob disease and Gertsmann-Str€ aussler-Scheinker syndrome represent two of the most common manifestations of prion-related pathologies. 10,11 An M/V polymorphism in position 129 of PrP is responsible for two different variants of CJD, 12 whereas stop-inducing mutations at positions Y145 and Q160 are related to Gertsmann-Str€ aussler-Scheinker-like phenotypes.…”