Protein Folding and Degradation

Introduction – Protein Folding and Degradation

Protein folding and degradation are fundamental processes that are essential for the proper function and maintenance of cells. Proteins are synthesized as linear polypeptide chains, but in order to carry out their biological functions, they must fold into specific three-dimensional structures. Misfolded or damaged proteins can be toxic to cells, so cells have developed mechanisms to recognize and degrade these proteins.

Protein folding involves the formation of various intramolecular interactions, such as hydrogen bonds, disulfide bonds, and hydrophobic interactions, that stabilize the protein in its native state. The folding process is aided by molecular chaperones, which are specialized proteins that assist in the folding of other proteins by preventing misfolding and aggregation.

Protein degradation is also critical for maintaining cellular homeostasis. Cells have developed several mechanisms to degrade unwanted or damaged proteins, including the ubiquitin-proteasome system and autophagy. The ubiquitin-proteasome system involves the attachment of a small protein called ubiquitin to target proteins, which marks them for degradation by the proteasome, a large protein complex that acts as a garbage disposal system for unwanted proteins. Autophagy is a process by which cells engulf damaged or unwanted proteins and other cellular components in a double-membrane structure called an autophagosome, which fuses with lysosomes to degrade the contents.

Defects in protein folding and degradation can lead to a variety of diseases, including neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, as well as cancer and other genetic disorders. Researchers are actively studying these processes to better understand their underlying mechanisms and develop new therapies for these diseases.

Folding

• Overview
  • required for a protein to achieve a proper tertiary protein structure
  • involves heat shock proteins (Hsp)
    • essential for normal protein folding
    • some function as chaperones and some function as chaperonins
  • the more mutated a protein, the more help it needs from chaperones
  • if a protein is not folding properly, a chaperone may send it directly for degradation
  • clinical relevance
    • cystic fibrosis
      • pathogenesis
        • 3 nucleotide deletion on chromosome 7
        • ΔF508 mutation in chloride channel (CFTR) ↓ stability of the protein and ↑ folding time 
        • instead of insertion into the plasma membrane the protein is degraded in the Golgi apparatus
        • ↓ chloride conductance results in ↓ Na⁺ and Cl reabsorption in sweat glands
      • presentation
        • ↓ water content of mucus which results in a thick mucus that cannot be cleared
          • respiratory infections
          • nasal polyps
          • malabsorption
          • meconium ileus
          • biliary cirrhosis
• Chaperones
  • types
    • Hsp70
      • associates with directly with the ribosome
      • hides hydrophobic regions of protein to allow for proper folding
      • ATP hydrolysis required
      • essential
    • Hsp90
      • used for fewer proteins than Hsp70
      • ATP hydrolysis required
      • essential
      • role in folding mutant proteins in cancer
• Chaperonins
  • group 1
    • Hsp60
      • ring shaped
      • ATP hydrolysis required
      • called GroEL/GroES in prokaryotes
      • peptide chain enters the cage and it is capped
      • once folded the cap is removed and the protein is released
  • group 2
    • TRiC/CCT
      • composed of 8 Hsp60s
      • similar function to GroEL/GroES
• required for folding of actin and tubulin

Degradation

• Ubiquitination
  • cell’s mechanism to mark a protein for destruction
  • mechanism
    • several copies of ubiquitin added to a misfolded/unneeded protein
    • polyubiquitinated protein enters the proteasome
    • protein hydrolyzed into peptide fragments
• Defects in destruction of misfolded proteins
  • inability to send degraded proteins to proteasome results in accumulation in ER
  • examples
    • α₁-antitrypsin (AAT) deficiency
      • normally synthesized by hepatocytes and exocytosed into circulation
        • inhibit proteases
      • in AAT deficiency misfolded α₁-antitrypsin accumulates in ER and damages hepatocytes
        • PAS+ granules
      • many genetic variations
        • MC are Z and S variants due to point mutations
        • co-dominant allelic expression
      • presentation
        • micronodular cirrhosis
        • fibrosis
• test with PCR

Function – Protein Folding and Degradation

Protein folding and degradation are essential processes that serve several critical functions in cells. Here are some of the key functions of these processes:

1. Maintenance of protein function: Proper protein folding is essential for proteins to carry out their biological functions. Misfolded or damaged proteins can lose their activity or even become toxic to cells. Protein folding mechanisms help ensure that proteins are properly folded and functional.
2. Quality control: Protein folding mechanisms serve as a quality control system, preventing misfolded or damaged proteins from accumulating in cells. Molecular chaperones and other quality control mechanisms help identify and refold misfolded proteins or target them for degradation.
3. Adaptation to stress: Cells can experience various types of stress, such as heat, oxidative stress, and nutrient deprivation, which can affect protein folding and function. Cells have developed mechanisms to adapt to these stresses, such as the induction of molecular chaperones or the activation of signaling pathways that promote protein folding and degradation.
4. Regulation of protein levels: Protein degradation mechanisms help regulate the levels of specific proteins in cells. The ubiquitin-proteasome system and autophagy can target specific proteins for degradation in response to changes in cellular conditions or signaling pathways.
5. Prevention of disease: Defects in protein folding and degradation can lead to the accumulation of misfolded or damaged proteins, which can contribute to the development of diseases such as neurodegenerative disorders, cancer, and genetic disorders. Understanding these processes and developing new therapies to modulate them is critical for the prevention and treatment of these diseases.

Overall, protein folding and degradation are essential processes that help ensure proper protein function, quality control, adaptation to stress, and prevention of disease.

Studies – Protein Folding and Degradation

Protein folding and degradation are the subject of extensive research, as understanding these processes is critical for understanding cellular function and the development of many diseases. Here are some examples of research studies related to protein folding and degradation:

1. Elucidating the mechanisms of protein folding: Researchers use a variety of techniques, such as X-ray crystallography, NMR spectroscopy, and cryo-electron microscopy, to study the structural and dynamic aspects of protein folding. By understanding the mechanisms of protein folding, researchers can develop new strategies to prevent or treat protein folding diseases.
2. Identification of molecular chaperones: Molecular chaperones are specialized proteins that assist in protein folding and prevent misfolding and aggregation. Researchers continue to identify new chaperones and study their mechanisms of action. Some chaperones are being developed as potential therapeutic targets for protein folding diseases.
3. Proteasome and autophagy regulation: Researchers are investigating the regulatory mechanisms of the ubiquitin-proteasome system and autophagy, including the roles of ubiquitin ligases and deubiquitinating enzymes in targeting specific proteins for degradation. Understanding these regulatory mechanisms is important for developing new therapies for diseases related to protein degradation.
4. Protein folding diseases: Many diseases are caused by defects in protein folding, such as Alzheimer’s disease, Parkinson’s disease, cystic fibrosis, and prion diseases. Researchers are studying the mechanisms underlying these diseases and developing new therapies to prevent or treat them. For example, small molecule drugs and gene therapies are being developed to target misfolded proteins and promote protein folding.
5. Protein degradation and cancer: Abnormal protein degradation is implicated in cancer development and progression. Researchers are investigating the roles of the ubiquitin-proteasome system and autophagy in cancer biology and developing new therapeutic strategies that target these processes.

Overall, protein folding and degradation are the subject of extensive research, and ongoing studies are providing new insights into these fundamental cellular processes and their roles in disease development and progression.

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