WKI Sales Training Feb 2014

22

2. Structure of Proteins

B. Prion diseases The prion protein (PrP) has been strongly implicated as the causative agent of transmissible spongiform encephalopathies (TSEs), including Creutzfeldt-Jakob disease in humans, scrapie in sheep, and bovine spongiform encephalopathy in cattle (popularly called “mad cow” dis- ease). After an extensive series of purification procedures, scientists were surprised to find that the infectivity of the agent causing scrapie in sheep was associated with a single protein species that was not complexed with detectable nucleic acid. This infectious protein is designated PrP Sc (Sc = scrapie). It is highly resistant to proteolytic degradation and tends to form insoluble aggregates of fibrils, similar to the amyloid found in some other diseases of the brain. A nonin- fectious form of PrP C (C = cellular), encoded by the same gene as the infectious agent, is present in normal mammalian brains on the surface of neurons and glial cells. Thus, PrP C is a host protein. No primary structure differences or alternate posttranslational modifica- tions have been found between the normal and the infectious forms of the protein. The key to becoming infectious apparently lies in changes in the three-dimensional conformation of PrP C . It has been observed that a number of α ‑helices present in noninfectious PrP C are replaced by β -sheets in the infectious form (Figure 2.14). It is presumably this conformational difference that confers relative resistance to proteolytic degradation of infectious prions and permits them to be distinguished from the normal PrP C in infected tissue. The infective agent is, thus, an altered version of a normal protein, which acts as a “template” for converting the normal protein to the pathogenic conformation. The TSEs are invariably fatal, and no treatment is currently available that can alter this outcome. VII. CHAPTER SUMMARY Central to understanding protein structure is the concept of the native conformation (Figure 2.15), which is the functional, fully folded protein structure (for example, an active enzyme or structural protein). The unique three-dimensional structure of the native conformation is determined by its primary structure , that is, its amino acid sequence. Interactions between the amino acid side chains guide the folding of the polypeptide chain to form secondary , tertiary , and (sometimes) quaternary structures, which cooperate in stabilizing the native conformation of the protein. In addition, a specialized group of proteins named chaperones is required for the proper folding of many species of proteins. Protein denaturation results in the unfolding and disorganization of the protein’s structure, which are not accompanied by hydrolysis of peptide bonds. Denaturation may be revers- ible or, more commonly, irreversible. Disease can occur when an appar- ently normal protein assumes a conformation that is cytotoxic, as in the case of Alzheimer disease and the transmissible spongiform encepha- lopathies ( TSEs ), including Creutzfeldt-Jakob disease . In Alzheimer disease, normal proteins, after abnormal chemical processing, take on a unique conformational state that leads to the formation of neurotoxic amy- loid β peptide ( A β ) assemblies consisting of β -pleated sheets. In TSEs, the infective agent is an altered version of a normal prion protein that acts as a “template” for converting normal protein to the pathogenic conformation.

1 Interaction of the infectious PrP molecule with a normal PrP causes the normal form to fold into the infectious form.

Noninfectious PrP C (contains α -helix)

Infectious PrP Sc (contains β -sheets)

Infectious PrP Sc (contains β -sheets)

2 These two molecules dissociate and convert two additional non- infectious PrP molecules to the infectious form.

Noninfectious PrP C (contains α -helix)

Noninfectious PrP C (contains α -helix)

3

This results in an exponential increase of the infectious form.

Figure 2.14 One proposed mechanism for multiplication of infectious prion agents. PrP = prion protein; PrP c = prion protein cellular; PrP Sc = prion protein scrapie.

02_Structure_proteins.indd 22

12/13/12 11:59 AM