Protein Folding

Protein Folding and Chaperones

Summary

Protein folding follows a funnel-shaped energy landscape toward the native state. Molecular chaperones (Hsp70, Hsp60, Hsp90) prevent aggregation and rescue misfolded intermediates through ATP-driven cycles.

Key Points

  • 1Sequence determines structure (Anfinsen), but folding is pathway-dependent
  • 2Energy landscape funnel guides folding toward native state
  • 3Hsp70, Hsp60, and Hsp90 are the major chaperone families
  • 4Co-translational folding couples synthesis to folding
  • 5Proteostasis network integrates folding and degradation

Protein folding and the chaperone systems that support it represent one of the most fundamental processes in cellular biology.

The Folding Problem

Anfinsen's Dogma

  • The amino acid sequence contains all information for folding
  • Demonstrated by ribonuclease A refolding experiments
  • Nobel Prize 1972

    • Levinthal's Paradox

  • Random conformational search would take astronomical time
  • Proteins fold in milliseconds to seconds
  • Resolution: folding follows directed pathways

    • The Energy Landscape

    Folding Funnel Model

  • Energy landscape resembles a funnel
  • Native state at the bottom (global minimum)
  • Multiple routes down the funnel
  • Ruggedness creates kinetic traps

    • Thermodynamic Considerations

  • ΔG = ΔH - TΔS determines stability
  • Hydrophobic effect provides primary driving force
  • Marginal stability: ΔG typically -5 to -15 kcal/mol

    • Molecular Chaperone Systems

    Hsp70 System

  • Binds exposed hydrophobic segments
  • ATP-dependent bind/release cycle
  • Co-chaperones: Hsp40 (substrate delivery), NEFs (nucleotide exchange)
  • Prevents aggregation, assists refolding

    • Chaperonins (Hsp60)

  • Barrel-shaped folding chambers
  • GroEL/GroES in bacteria, TRiC in eukaryotes
  • Isolates single proteins for folding
  • Essential for ~10-15% of proteins

    • Hsp90

  • Specialized for signaling proteins
  • Kinases, receptors, transcription factors
  • Complex co-chaperone network
  • Cancer therapy target

    • Co-translational Folding

    Ribosome-Associated Chaperones

  • Trigger Factor (bacteria)
  • NAC, RAC (eukaryotes)
  • Protect nascent chains during synthesis

    • Vectorial Folding

  • N-terminus folds first
  • Sequential domain folding
  • Prevents inter-domain misfolding

    • When Folding Fails

    Aggregation

  • Exposed hydrophobic surfaces associate
  • Amorphous aggregates or ordered amyloids
  • Often toxic to cells

    • Proteostasis Network

  • Chaperones + degradation systems
  • UPS for soluble proteins
  • Autophagy for aggregates
  • Declines with aging
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