Tertiary and Quaternary Structures

Tertiary Structure - 3D Folding Fun

• Overall 3D shape of one polypeptide chain; crucial for biological function.
• Stabilized by R-group (side chain) interactions.
• Key Bonds & Forces:
  • Hydrophobic interactions: Non-polar residues cluster inwards (core); major driver.
  • Disulfide bonds (-S-S-): Strong covalent links (Cys-Cys).
  • Hydrogen bonds: Between polar R-groups.
  • Ionic bonds (salt bridges): Between charged R-groups.
  • Van der Waals forces: Weak, transient attractions.
• Domains: Stable, independently folding regions with specific functions.

⭐ Hydrophobic interactions are the primary driving force for the folding and stability of tertiary structures.

Protein Folding & Denaturation - Helpers & Spoilers

• Folding: Polypeptide attains native, functional 3D structure.
  • Driven by its primary amino acid sequence (Anfinsen's dogma).
  • Chaperones (e.g., Hsp70, Hsp60): Assist correct folding, prevent misfolding and aggregation.
  • Molten globule: A key compact, partially folded intermediate.
• Denaturation: Loss of native 2°/3°/4° structure & biological function. Primary structure preserved.
  • Agents: Heat, pH extremes, organic solvents, urea, guanidinium HCl, heavy metals (Pb, Hg), reducing agents (β-mercaptoethanol for S-S bonds).

⭐ Prion diseases (e.g., CJD): Misfolded PrPSc induces conformational change in normal PrPC, leading to aggregation.

Quaternary Structure - Subunit Synergy

• Arrangement of multiple polypeptide chains (subunits) into a functional protein complex.
• Subunits held by non-covalent bonds (hydrophobic, H-bonds, ionic) and sometimes disulfide bonds.
• Types: Homomeric (identical subunits) or Heteromeric (different subunits).
• Allows for cooperativity (e.g., Hemoglobin's oxygen binding) and allosteric regulation, enhancing functional versatility.

  ⭐ Hemoglobin is a tetramer with two α and two β subunits ($α_2β_2$); its cooperative binding of oxygen is a key example of subunit synergy.

Hemoglobin & Cooperativity - Cooperative Crew

Hb ($α_2β_2$ tetramer) shows quaternary structure-dependent O₂ transport.

• Cooperativity: O₂ binding to one heme ↑ affinity of others. Sigmoidal O₂ dissociation curve (ODC).
  • T (tense): Low O₂ affinity (deoxy-Hb).
  • R (relaxed): High O₂ affinity (oxy-Hb).
• Allosteric Effectors (Shift ODC Right → ↓ Affinity):
  • ↑2,3-BPG, ↑H⁺ (Bohr effect), ↑CO₂, ↑Temperature.
  • 📌 CADET, face Right! (CO₂, Acid, 2,3-DPG, Exercise, Temp).
• Left Shift (↑ Affinity): CO, ↓H⁺, ↓CO₂, ↓Temp. Fetal Hb (HbF).

⭐ Bohr effect: ↓pH (↑H⁺) or ↑CO₂ stabilizes T-state, promoting O₂ release from Hb in tissues (ODC right shift).

Protein Misfolding Diseases - When Proteins Go Rogue

• Misfolded proteins: lose normal function, gain toxic properties, aggregate.
• Leads to cellular stress, apoptosis, and tissue damage.
• Failure of chaperones or ubiquitin-proteasome system.
• Amyloidosis: Pathological deposition of insoluble fibrillar proteins.
  • Alzheimer's Disease: Aβ peptide, Tau protein.
  • Parkinson's Disease: α-synuclein.
• Prion Diseases: (e.g., CJD, Kuru)
  • Infectious $PrP^{Sc}$ (misfolded prion protein) induces misfolding of normal $PrP^C$.

⭐ Alzheimer's disease is characterized by extracellular amyloid-β plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein.

High‑Yield Points - ⚡ Biggest Takeaways

• Tertiary structure: 3D folding of one polypeptide; bonds: disulfide, hydrophobic, H-bonds, ionic.
• Domains: Independently folded functional/structural units in tertiary structure.
• Chaperones (e.g., Hsp70) assist correct protein folding, prevent aggregation.
• Protein misfolding causes diseases: Alzheimer's (Aβ), prion diseases (PrPSc).
• Quaternary structure: Assembly of multiple subunits (e.g., hemoglobin); stabilized by non-covalent forces, interchain disulfides.
• Hemoglobin's cooperativity: Key example of quaternary structure function.