Misfolded

Misfolded describes a protein that fails to attain or maintain its native, functional three-dimensional structure. A misfolded protein may be partially folded or adopt an aberrant conformation that is not compatible with its physiological role. Misfolding can result from genetic mutations that alter amino acid sequence, errors during translation, or post-translational modifications, as well as environmental stress such as elevated temperature, pH changes, or oxidative conditions. Misfolded proteins can expose hydrophobic surfaces and form nonnative interactions, increasing the likelihood of aggregation.

In cells, quality control systems strive to prevent misfolding from causing harm. Molecular chaperones assist correct folding, while misfolded species are often targeted for degradation through the ubiquitin-proteasome system or autophagy. If these pathways are compromised, misfolded proteins may accumulate, causing cellular stress or cytotoxicity. Aggregates and amyloid structures are associated with various diseases, including prion diseases, Alzheimer's, Parkinson's, and Huntington's diseases. Misfolding can also underlie functional deficits in secreted or membrane proteins, such as CFTR in cystic fibrosis.

Researchers study misfolding with techniques such as conformation-specific antibodies, spectroscopy, cryo-electron microscopy, and other biophysical methods. Understanding misfolding helps in developing therapies that stabilize native folds, enhance protein clearance, or interfere with aggregation, including pharmacological chaperones and modulators of proteostasis.