Week 10 A - Proteosome and Autophagy

Learning Outcomes

• Understanding of protein homeostasis and its significance.
• Role of the proteasome in protein removal.
• Impact of post-translational modification, specifically ubiquitinylation, on protein turnover.
• Connection between the proteasome and immune system detection of self versus non-self.
• Autophagy's role in clearing protein aggregates and damaged organelles.

Protein Production

• Process:
  • mRNA -> Nascent protein -> ER signal sequence.
  • Proteins are synthesized in the endoplasmic reticulum and processed through the Golgi apparatus to reach their destinations (e.g., cell surface, lysosome).

Protein Turnover

• Definition: Protein turnover relates to the balance between protein synthesis and degradation.
• Half-life: Each protein has a specific half-life (T1/2), ranging from minutes to weeks.
• Factors affecting half-life include post-translational modifications and aging.

Protein Homeostasis

• Normal Condition: Balance between protein synthesis and degradation for cellular health.
• Disruption: Imbalances can lead to diseases like Parkinson's (α-synuclein misfolding) and Alzheimer's (increased Aβ peptide).
• Consequences: Increased protein degradation can be seen in conditions like cystic fibrosis.

Monitoring Protein Quality

• Error Rate: Higher translation errors (1 error per 10 proteins) compared to transcription.
• Chaperone Proteins: Hsp60 and its co-chaperones (Hsp10) assist in proper protein folding.

Proteasome

• Function: Found in the cytosol and nucleus. Responsible for degrading damaged, misfolded, or unneeded proteins.
• Composition: The 26S proteasome, which includes the 20S core and regulatory complexes (like 19S cap).
• Role of Ubiquitinylation: Substrates are tagged for degradation by attachment of ubiquitin, mediated by E1 (activating), E2 (conjugating), and E3 (ligase) enzymes.

Forms of the Proteasome

• 20S Proteasome: Core unit that performs proteolysis.
• 26S Proteasome: Includes regulatory particles that recognize polyubiquitinated substrates.

Ubiquitinylation

• Definition: A post-translational modification where ubiquitin (a 76 amino acid protein) is attached to lysine residues of target proteins, flagging them for degradation.
• Process: Coordinated action of E1, E2, and E3 enzymes in ubiquitin attachment.

Recognition and Degradation of Ubiquitinated Proteins

• Mechanism: The 19S regulatory particle recognizes ubiquitin chains and unfolds proteins for entry into the catalytic core.

Autophagy

• Definition: A cellular process for degrading and recycling cellular components.
• Types: Includes macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA).
• Regulation Factors: mTOR is a key regulator; nutrient availability affects autophagy.
• Physiological Functions: Autophagy plays roles in immune response, cancer, aging, and neurodegeneration.

Pathways Involved in Autophagy Regulation

• ULK1 Complex: Activation in response to nutrient deprivation.
• Vps34-Beclin1 Complex: Essential for phagophore formation.
• mTOR and AMPK Pathways: Key nutrients and energy sensors that regulate autophagy.