Prion Protein and Its Conformational Conversion: A Structural Perspective

Abstract

The key molecular event in the pathogenesis of prion diseases is the conformational conversion of a cellular prion protein, PrP(C), into a misfolded form, PrP(Sc). In contrast to PrP(C) that is monomeric and α-helical, PrP(Sc) is oligomeric in nature and rich in β-sheet structure. According to the "protein-only" model, PrP(Sc) itself represents the infectious prion agent responsible for transmissibility of prion disorders. While this model is supported by rapidly growing experimental data, detailed mechanistic and structural aspects of prion protein conversion remain enigmatic. In this chapter we describe recent advances in understanding biophysical and biochemical aspects of prion diseases, with a special focus on structural underpinnings of prion protein conversion, the structural basis of prion strains, and generation of prion infectivity in vitro from bacterially-expressed recombinant PrP.

Infrared Microspectroscopy Detects Protein Misfolding Cyclic Amplification (PMCA)-induced Conformational Alterations in Hamster Scrapie Progeny Seeds

“…The amide I band used in our study, in which secondary structure elements, such as ␣-helix, ␤-sheet, or turns and loops, absorb IR light at different wavelengths, has been established as the most useful band for the analysis of secondary protein structure (for details, see Refs. [37][38][39].…”

“…In this context, it has to be noted that the association between specific IR absorption bands and ␣-helical structure elements in PrP is currently under discussion (38,40). For our study, however, this is not critical because we focused on IR bands that are assigned to ␤-sheets according to the conventional practice described in the literature (37,39). We could detect conformational differences for ␤-sheet structures in the structure-sensitive amide I region (1610 -1700 cm Ϫ1 ) between the tested prion isoforms.…”

Transformation

“…Larger conformational changes have also been described, but they often involve transitions between structured and unstructured regions. [25][26][27][28] However, the complete conformational switch from one state with stable secondary structure elements (all-α-helical fold) to another state with completely different stable secondary structure elements (all-β structure) surpasses the extent of all structural transitions that have been described so far, singling RfaH out as a thus far unique system. NTD that breaks the salt bridge to Arg138 in the CTD, without altering the CTD itself.…”

“…Never before has a protein been described that simultaneously changes both its complete stable topology of conservative secondary structure elements and its function. This includes prion proteins 26 and the β-amyloid A4 peptide, 35 which both undergo large conformational changes but do not coexist in two forms in identical gel filtration as well as NMR spectroscopy, and chemical shift mapping indicated that RfaH CTD and NusG CTD use similar sets of interactions to bind S10. Targeted ChIP-chip analysis and mass spectroscopy identification of E. coli proteins interacting with RfaH showed that S10 is associated with the RfaH-controlled rfb operon and with RfaH, respectively, lending support to physiological relevance of these contacts.…”

Roles of Endoplasmic Reticulum Stress in Neurodegenerative Diseases

“…Prion protein (PrP) exists in at least two conformational states, the normal cellular form (PrP c ) and an abnormal infective form (PrP Sc ). The abnormal PrP Sc differs from the normal cellular form only in its three-dimensional conformation, having a higher β-sheet structure than the native protein [64][65][66]. Both PrP c and PrP Sc are involved in neurodegeneration associated with prion diseases [67][68][69][70][71].…”