Advanced Topics

Quaternary Structure and Allostery

Summary

Quaternary structure describes the assembly of multiple polypeptide subunits into functional protein complexes. Allostery is the phenomenon where ligand binding at one site affects activity at a distant site, enabling sophisticated regulation of protein function.

Key Points

  • 1Quaternary structure: assembly of multiple subunits into complexes
  • 2Allostery: ligand binding at one site affects distant sites
  • 3MWC (concerted) and KNF (sequential) models explain cooperativity
  • 4Hemoglobin is the classic example of allosteric regulation

Quaternary structure and allostery represent the highest levels of protein organization, enabling complex regulatory mechanisms essential for cellular function.

Quaternary Structure Fundamentals

Definition and Scope

Quaternary structure refers to the arrangement of multiple polypeptide chains (subunits) into a functional protein complex:

- Oligomers: Proteins with multiple subunits

- Homomers: Identical subunits (e.g., homodimers, homotetramers)

- Heteromers: Different subunits (e.g., hemoglobin α₂β₂)

Subunit Interfaces

The interactions holding subunits together include:

1. Hydrophobic contacts: Burial of nonpolar surfaces

2. Hydrogen bonds: Between backbone and side chain atoms

3. Salt bridges: Electrostatic interactions between charged residues

4. Disulfide bonds: Covalent links (less common)

Symmetry in Oligomers

Most oligomeric proteins exhibit symmetry:

- Cyclic symmetry (Cₙ): Rotational symmetry only

- Dihedral symmetry (Dₙ): Rotational plus 2-fold perpendicular axes

- Cubic symmetry: Higher-order arrangements (e.g., viral capsids)

Allostery: Regulation at a Distance

The Allosteric Concept

Allostery describes how binding of a molecule (effector) at one site affects protein function at a spatially distinct site:

- Allosteric activators: Increase activity

- Allosteric inhibitors: Decrease activity

- Homotropic effects: Same ligand affects multiple sites

- Heterotropic effects: Different ligands at different sites

Classical Models

#### MWC (Monod-Wyman-Changeux) Model

Also called the concerted model:

- Protein exists in two states: T (tense) and R (relaxed)

  • All subunits change conformation simultaneously
  • Ligand preferentially binds one state, shifting equilibrium
  • Explains sigmoidal binding curves and cooperativity

    • #### KNF (Koshland-Némethy-Filmer) Model

    Also called the sequential model:

  • Subunits change conformation independently
  • Ligand binding induces conformational change in that subunit
  • Changes propagate to neighboring subunits
  • More flexible but complex

    • Hemoglobin: The Paradigm

    Hemoglobin exemplifies both quaternary structure and allostery:

    #### Cooperative Oxygen Binding

    - Sigmoidal binding curve: Low affinity initially, increases with each O₂ bound

    - Hill coefficient ~2.8: Indicates strong positive cooperativity

  • T-state (deoxy): Low O₂ affinity
  • R-state (oxy): High O₂ affinity

    • #### Allosteric Effectors

    - 2,3-BPG: Stabilizes T-state, reduces O₂ affinity (altitude adaptation)

    - CO₂ and H⁺ (Bohr effect): Promote O₂ release in tissues

    - Chloride ions: Additional modulators

    Modern Understanding of Allostery

    The Ensemble View

    Contemporary models emphasize conformational ensembles:

  • Proteins exist as populations of interconverting conformers
  • Allosteric effectors shift population distributions
  • No need for distinct "states" – continuous landscapes

    • Intrinsic Disorder and Allostery

    IDPs can exhibit allostery through:

    - Coupled folding and binding

    - Entropy redistribution

    - Allosteric coupling without structural change

    Allostery in Drug Design

    Allosteric sites offer advantages as drug targets:

  • Often less conserved than active sites
  • Can achieve modulation rather than complete inhibition
  • Reduced competition with natural substrates
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