Cell Biology Chapter 2 Chaperons for protein folding

Protein Folding Overview

• Understanding protein folding is still an area of active research.

• Is the folding process the same for each protein of the same type?

• Questions remain about the timing and sequence of structural formations during folding:

  • Does the secondary structure form first or later in the process?

• Many proteins require assistance to fold correctly.

Challenges in Protein Folding

• Hydrophobic Regions:

  • These regions tend to aggregate,

  • Misfolding: occurs through self-aggregation or aggregation with other hydrophobic materials in the cell.

Molecular Chaperones to the Rescue

• Functionality:

  • Molecular chaperones bind to and sequester hydrophobic regions to prevent aggregation, promoting proper folding.

  • Key chaperones include the Hsp70 family which operates co-translationally (as proteins are being synthesized).

  • This assists proteins in achieving their functional conformation (native structure).

  • Refer to Figure 2.46 for details.

Chaperonins

• Hsp60 Family of Proteins:

  • These proteins assist in the folding of polypeptides.

  • e.g. TRiC

  • The GroEL member is well-studied concerning virus assembly

Structure of GroEL

• Composed of 14 polypeptides organized into two stacked rings.

• The GroES protein acts as a cap for GroEL, enhancing its functionality—refer to Experimental Pathways 2.14 for visuals.

• provide favorable conditions for protein folding

• GroEL:

  • 14 polypeptide → stacked

• GroES:

  • acts as a “cap” in bacteria

Mechanism of Action of Chaperonins

• Without GroES, the GroEL chamber remains hydrophobic, allowing binding to unfolded proteins' hydrophobic regions.

  • When GroES binds to GroEL:

    • it enlarges the chamber, transforming it into a hydrophilic environment.

    • requires ATP breakdown (hydrolysis) for energy

  • This change facilitates the release of the protein, allowing it to attempt proper folding

GroEL/GroES Assisted Folding Process

• The folding steps involving GroEL and GroES can be represented as follows:

  • Sequence of ATP binding and hydrolysis steps leads to binding, folding, and potential release of misfolded proteins, as shown in Experimental Pathways

Importance of Proper Protein Folding

• Misfolded proteins can cause several diseases, including:

  • Cystic fibrosis,

  • Parkinson’s disease,

  • Alzheimer’s disease,

  • Huntington’s disease.

  • Further reading in the provided online source.

Common Features in Protein Folding Diseases

• Structural Changes:

  • Transition from α-helix to β-sheet is a notable change characteristic of misfolded proteins.

• Mechanisms may involve:

  • Formation of aggregates

  • Dimerization and oligomerization leading to higher order aggregates (as visualized in the figures).

Role of Hsp70 Family of Chaperones

• Named after Heat Shock Protein 70, as they are activated by stress conditions (such as heat-shock).

• When cells encounter heat shocks, proteins typically:

  • Unfold and may become denatured.

Response of Hsp70 Chaperones

• During heat stress:

  • They assist in refolding proteins, binding to hydrophobic regions to prevent aggregation. Help refold by also forming tiny molds that are the exact shape of every protein in the cell

  • This process is critical for cell survival and recovery.

  • The chaperone activity is a constant cellular feature, but they are upregulated during stress events.

Conclusion on Molecular Chaperones

• Molecular chaperones play a crucial role in protein homeostasis.

• They are always present in the cell and are synthesized in greater quantities (up regulated) during stress, emphasizing their importance in cellular function and health.