Alternatively Folded Proteins Are Implicated in Slowly Developing Diseases

As noted earlier, each protein species normally folds I into a single, energetically favorable conformation h'lUiHHii'H js specified by its amino acid sequence. Recent evidence suggests, however, that a protein may fold into an alternative three-dimensional structure as the result of mutations, inappropriate post-translational modification, or other as-yet-unidentified reasons. Such "misfolding" not only leads to a loss of the normal function of the protein but also marks it for proteolytic degradation. The subsequent accumulation of proteolytic fragments contributes to certain degenerative diseases characterized by the presence of insoluble protein plaques in various organs, including the liver and brain. I

Some neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease in humans and transmissible spongiform encephalopathy ("mad cow" disease) in cows

▲ EXPERIMENTAL FIGURE 3-14 Alzheimer's disease is characterized by the formation of insoluble plaques composed of amyloid protein. (a) At low resolution, an amyloid plaque in the brain of an Alzheimer's patient appears as a tangle of filaments. (b) The regular structure of filaments from plaques is revealed in the atomic force microscope. Proteolysis of the naturally occurring amyloid precursor protein yields a short fragment, called p-amyloid protein, that for unknown reasons changes from an a-helical to a p-sheet conformation. This alternative structure aggregates into the highly stable filaments (amyloid) found in plaques. Similar pathologic changes in other proteins cause other degenerative diseases. [Courtesy of K. Kosik.]

and sheep, are marked by the formation of tangled filamentous plaques in a deteriorating brain (Figure 3-14). The amyloid filaments composing these structures derive from abundant natural proteins such as amyloid precursor protein, which is embedded in the plasma membrane, Tau, a microtubule-binding protein, and prion protein, an "infectious" protein whose inheritance follows Mendelian genetics. Influenced by unknown causes, these a helix-containing proteins or their proteolytic fragments fold into alternative p sheet-containing structures that polymerize into very stable filaments. Whether the extracellular deposits of these filaments or the soluble alternatively folded proteins are toxic to the cell is unclear.

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