Protein Interactions & Misfolding Summary

Ubiquitous & Essential for:

• Gene regulation

• Cell signaling

• Enzyme function

• Structural integrity

• Each eukaryotic protein: ~6–8 partners

• Can be transient or stable, location-dependent

Examples

• Haemoglobin – cooperative O₂ binding

• Chaperones (GroEL/GroES) – prevent misfolding

• ATP Synthase – rotating complex, energy production

• Signalling – G-proteins, insulin receptors

• Transcription regulators – form large complexes

🤝 Types of Protein Interactions

1. Extensive surface contacts

2. Linear motifs (short unstructured peptides)

3. Modular domains (e.g., fibronectin)

Forces involved:

• Hydrophobic burial

• H-bonding

• Salt bridges (ionic)

• Shape & charge complementarity

⚠ Protein Aggregation

• Edge β-strands: prone to form unwanted interactions

  • β-strand addition = β from one protein adds to sheet of another

• Fibronectin example: exploited by S. aureus

⚔ Natural Protection Mechanisms

• Fold protection (e.g. β-barrels)

• Loops shielding strand edges

• β-bulges – distort sheet, disrupt interaction

• Proline/Trp residues – induce kinks

• Charged residues – repel interaction

• Short β-strands – limit aggregation

🧠 Protein Misfolding Diseases (Prion Diseases)

Key Diseases:

• CJD – human, sporadic/inherited/acquired

• vCJD – from BSE (mad cow)

• Scrapie – sheep/goats

• CWD – deer

• Kuru – cannibalism (PNG)

• GSS, Fatal Familial Insomnia – inherited

Key Points:

• PrP (Prion Protein) causes disease via misfolding

  • PrPᶜ: normal, α-helical, monomeric

  • PrPˢᶜ: misfolded, β-sheet rich, aggregates

  • Resistant to proteinase K, seeds further misfolding

• Infectious even without nucleic acids

  • Supports "Protein Only Hypothesis"

🔁 Conversion Models

1. Nucleation model

   • Oligomers act as seeds for aggregation

2. Template-assisted model

   • PrPᶜ binds PrPˢᶜ → refolds into PrPˢᶜ

Species Barrier

• PrP must match host's sequence to propagate

• Explains limited cross-species infection

🧪 Structure of PrP

• N-terminal: disordered, Cu²⁺ binding (octapeptide repeats)

• C-terminal: structured, α/β fold

  • Mutations here linked to disease (e.g., E200K, Q212P)

• Attached to membrane via GPI anchor

🧱 Amyloids

• Protein aggregates, 80–100 Å, fibrous, insoluble

• Form cross-β sheets: parallel β-sheets in-register

  • Stabilized by steric zippers (hydrophobic interface)

  • Self-seeding, polymorphic

Diagnostic:

• Congo red birefringence, X-ray diffraction

🧠 Alzheimer’s Disease

• Caused by Aβ peptide (40–42 aa)

• Derived from AβPP, forms amyloid fibrils

• Protofilaments → plaques near neurons

• Common fibril structure despite varied protein sources

🏞 Protein Folding Landscape

• Funnel-like energy landscape

• Aggregation occurs due to intermolecular contacts

• Misfolding traps protein in aggregation-prone states

🧬 Summary