Conformational Diseases and Structure-Toxicity Relationships: Lessons from Prion-Derived Peptides

Abstract

The physiological form of the prion protein is normally expressed in mammalian cell and is highly conserved among species, although its role in cellular function remains elusive. Available evidence suggests that this protein is essential for neuronal integrity in the brain, possibly with a role in copper metabolism and cellular response to oxidative stress. In prion diseases, the benign cellular form of the protein is converted into an insoluble, protease-resistant abnormal scrapie form. This conversion parallels a conformational change of the polypeptide from a predominantly alpha-helical to a highly beta-sheet secondary structure. The scrapie form accumulates in the central nervous system of affected individuals, and its protease-resistant core aggregates into amyloid fibrils outside the cell. The pathogenesis and molecular basis of the nerve cell loss that accompanies this process are not understood. Limited structural information is available on aggregate formation by this protein as the possible cause of these diseases and on its toxicity. A large amount of structure-activity studies is based on the prion fragment approach, but the resulting information is often difficult to untangle. This overview focuses on the most relevant structural and functional aspects of the prion-induced conformational disease linked to peptides derived from the unstructured N-terminal and globular C-terminal domains.

NMR Structure and CD Titration with Metal Cations of Human Prionα2-Helix-Related Peptides

“…Concerning the role played by metal cations in the - isomerisation, we have shown that the use of the α -helix-inducer TFE to force peptides into a conformation close to the helical one that has been found in may lead to conclusions different from those that can be obtained studying metal cation interaction with peptides in buffer solution. To embed our results in the body of data on PrP structure and function, it is worth considering that the three-dimensional architecture of consists of an unstructured leading tail encompassing residues 23–125 and a C-terminus globular domain, in which residues 126–231 are organized in three α -helices and a two-stranded β -sheet [ 55 , 56 ]. Although it is currently believed that the major structural modifications involved in PrP protein misfolding are located in the unstructured N-terminal region, the present work seems to provide further support to evidence accumulated in the literature that the two prion domains play a different role in the prion conversion, stressing that the N-terminal domain is likely the natural target of metal binding; see [ 57 , 58 ] and references cited therein.…”

Copper Binding Extrinsic to the Octarepeat Region in the Prion Protein

“…Fig. (1) highlights important structural features, as well as documented and potential copper binding sites [27-31]. The octarepeat region, with its four histidine containing octapeptide segments is most often the focus of study, however, as noted above, other sites have also been identified as potential copper binding regions.…”

Perivascular Accumulation of β-Sheet-Rich Proteins in Offspring Brain following Maternal Exposure to Carbon Black Nanoparticles

“…In Huntington disease, conformation of huntingtin protein is changed into β-sheet-rich structures that aggregate into potentially toxic oligomeric species and fibril structures ( Smaoui et al, 2016 ). The secondary structure of prion proteins that induce the severe conformational diseases of the brain, Creutzfeldt-Jakob disease and mad cow disease, clearly changes from α-helix to β-sheet-rich ( Ronga et al, 2007 ; Baskakov, 2009 ; Coleman et al, 2009 ). Thus, β-sheet-rich proteins may be key factors in the development of neurodegenerative disease.…”