Amyloid Fibrils

Protein misfolding occurs through several mechanisms: mutations that make the original protein shape less favorable, inadequate cellular oversight when chaperones or proteasomes malfunction due to aging or disease, and extrinsic factors like physical or chemical changes in the cytoplasm. Misfolded proteins expose hydrophobic segments that become insoluble in water, triggering aggregation into amyloid fibrils.

Hydrophobic segments normally folded into alpha-helices can assemble into beta-sheets. Hundreds of beta-sheets in identical misfolded proteins form hydrogen bonds and stack together. Two closely-packed stacks of beta-sheets associate to form cross-beta filaments, where individual beta-sheets lie perpendicular to the central axis. These filaments aggregate to form amyloid fibrils.

Chaperone proteins guide proteins to fold correctly into energetically-favorable structures with hydrophobic amino acids inside and charged or polar amino acids outside. When chaperones function properly, they prevent misfolding. However, when chaperones malfunction due to aging or disease, proteins remain in abnormal shapes and can accumulate into amyloid fibrils.

Neurodegenerative conditions like Alzheimer's and Parkinson's diseases show amyloid fibril accumulation. Prion diseases, including Creutzfeldt-Jakob disease in humans and Bovine spongiform encephalopathy (mad cow disease), also involve amyloid fibril formation. These transmissible prion diseases cause fatal neurodegeneration when misfolded PrP proteins convert normal PrPs into abnormal shapes.

Not all amyloid fibrils are harmful. Some bacteria use amyloid fibrils on their surfaces to create protective biofilms. Eukaryotes build reversible amyloid fibrils to pack and store secretory proteins until the cell needs to release them. Understanding these reversible amyloids can help develop treatments for irreversible amyloid aggregates associated with disease.

Misfolded PrP proteins, a neural membrane protein, can convert normal PrPs into abnormal shapes. All PrPs eventually assume the aberrant structure containing beta-sheets, causing them to aggregate and form amyloid fibrils. This transmissible form of amyloid formation is associated with fatal neurodegeneration in prion diseases.

Properly folded proteins maintain hydrophobic amino acids inside and charged or polar amino acids outside. When proteins misfold, hydrophobic segments become exposed and insoluble. These segments can form beta-sheets that stack into cross-beta filaments, which aggregate into amyloid fibrils. Understanding globular and fibrous proteins is essential to comprehending how structural disruption leads to fibril formation.