3.9:
Amyloid Fibrils
Proteins fold into energetically-favorable structures, with their hydrophobic amino acids on the inside and their charged and polar amino acids on the outside. Some proteins fold easily on their own but many are guided to fold correctly by proteins called chaperones.
Sometimes proteins fold into incorrect shapes, often referred to as misfolded proteins, which are degraded by the proteasome.
Inadequate cellular oversight, such as non-functioning chaperones or proteasomes due to aging or disease, can cause proteins to stay in abnormal shapes.
Mutations can cause protein misfolding if the original protein shape becomes less favorable.
Extrinsic factors, such as physical or chemical changes in the cytoplasm, force properly-folded proteins into new structures, suitable for the new environment.
Whatever the mechanism, misfolding can expose short, hydrophobic segments of a protein causing it to become insoluble in water. Some of these hydrophobic segments that normally fold into alpha-helices can assemble into beta-sheets.
Hundreds of beta-sheets in identical misfolded proteins form hydrogen bonds and stack to form long filaments. Two closely-packed stacks of beta-sheets associate to form a cross-beta filament.
In this structure, individual beta-sheets lie perpendicular to the central axis. These filaments can aggregate to form amyloid fibrils.
Accumulation of amyloid fibrils has been observed in certain neurodegenerative conditions, such as in Alzheimer's and Parkinson's diseases. Prion diseases, such as Creutzfeldt-Jacob disease in humans and Bovine spongiform encephalopathy, commonly known as mad cow disease, also involve the formation of amyloid fibrils.
One particular prion protein, PrP, is a neural membrane protein. Misfolded PrPs can convert normal PrPs into abnormal shapes. All PrPs eventually assume the aberrant structure.
The misfolded PrPs contain beta-sheets, and thus tend to aggregate and form amyloid fibrils. This transmissible form of amyloid formation is associated with fatal neurodegeneration.
However, not all amyloid fibrils are harmful. Some bacteria use amyloid fibrils on their surfaces to create protective biofilms. Moreover, eukaryotes build reversible amyloid fibrils to pack and store secretory proteins until the cell needs to release them.
Understanding these reversible amyloids can help us develop treatments for irreversible amyloid aggregates.
3.9:
Amyloid Fibrils
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to identify cellulose, and concluded the deposit was some type of carbohydrate. He named the deposits amyloid from the Greek word amylon and the Latin amylum for starch. Even though Friedrich and Kekule discovered the aggregates were mostly protein, only a few years later, in 1859, the misnomer continues to be used. Originally, fibrils were thought to form only outside the cells, but more recently, amyloid has been shown to disrupt intracellular functions.
Amyloid disorders are associated with different protein aggregates. Despite the differences in the amino acid sequences and structures of the disease-causing proteins, a characteristic feature of amyloid fibers is stacked β-sheets. The formation of these insoluble fibrils from soluble proteins occurs through the production of a partially unfolded intermediate. This intermediate is thermodynamically unfavorable and rapidly progresses to a stable polymer.
Fibrils and other aggregates, like plaques, are characteristic features of diseases such as Alzheimer’s and Parkinson’s. However, the exact mechanism of neurodegeneration and whether the fibrils are the cause or a symptom is still being debated. Other diseases associated with amyloid fibrils are prion diseases, a group of fatal neurodegenerative disorders known to affect animals and humans. They are also known as transmissible spongiform encephalopathies (TSEs). These disorders can arise spontaneously via an inherited mutation and can be transmitted to others by way of infection. A typical example of prion disease is Bovine spongiform encephalopathy, also known as mad cow disease, a neurodegenerative disease in cattle. This disease can be transmitted to humans that consume the infected meat, where it is called Creutzfeldt-Jakob disease.
Leitura Sugerida
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