Summary
Protein misfolding occurs when a polypeptide chain fails to adopt its functional native 3D conformation. Misfolded proteins expose hydrophobic residues, driving aggregation. The most pathological form is the amyloid fibril, characterized by a cross-β spine structure.
Key Points
- 1Misfolding exposes normally buried hydrophobic residues
- 2Amyloid fibrils have characteristic cross-β spine structure
- 3Aggregation follows nucleation-dependent kinetics
- 4Soluble oligomers often more toxic than mature fibrils
Protein misfolding and aggregation represent a fundamental failure of the protein folding process with severe pathological consequences.
Mechanisms of Misfolding
Proteins can misfold due to:
- Mutations: Altering the amino acid sequence and destabilizing the native state
- Environmental stress: Heat, oxidative stress, pH changes
- Marginal stability: The native state is only slightly more stable than misfolded states
- Overwhelmed proteostasis: When chaperones and degradation systems are saturated
The Aggregation Pathway
Misfolded proteins characteristically expose hydrophobic residues that would normally be buried. This drives:
1. Oligomer formation: Small, often toxic assemblies
2. Protofibril formation: Extended, β-sheet-rich structures
3. Mature fibril formation: Highly stable amyloid structures
Amyloid Fibrils
The most stable and pathological aggregate form is the amyloid fibril:
Cross-β Spine Structure
- β-strands run perpendicular to the fibril axis
- Backbone hydrogen bonds run parallel to the axis
Characteristic Properties
Nucleation-Dependent Kinetics
Aggregation typically follows a sigmoidal kinetic profile:
1. Lag phase: Slow, unfavorable nucleus formation (primary nucleation)
2. Growth phase: Rapid elongation once nuclei form
3. Plateau: Monomer depletion
The Proteostasis Network
Cells combat misfolding through the proteostasis network:
- Chaperones: Hsp70, Hsp90, chaperonins
- Ubiquitin-Proteasome System (UPS): Degradation of misfolded monomers
- Autophagy: Clearance of larger aggregates
Proteinopathies
Failure of proteostasis leads to diseases including:
- Alzheimer's disease: Aβ plaques and tau tangles
- Parkinson's disease: α-synuclein Lewy bodies
- Huntington's disease: polyQ aggregates
- Prion diseases: PrP^Sc amyloid