Recording-2025-03-11T15:12:36.055Z

Protein Synthesis and Translocation

• Translation Mechanism:

  • Driven by the translation process itself as proteins elongate.

  • Post-translational translocation involves a molecular ratchet mechanism aiding in the protein's movement into the endoplasmic reticulum (ER).

• Glycosylation:

  • Proteins entering the ER may undergo glycosylation via specific enzymes near the Sec61 translocon.

  • Glycosylation involves:

    • Addition of glucose sugars.

    • Formation of a mannose core.

    • Terminal addition of N-acetylglucosamine.

Protein Folding and Chaperones

• Chaperone Proteins:

  • After synthesis, proteins like BiP (Binding immunoglobulin Protein) assist in proper folding within the ER.

  • Calnexin and other chaperones are crucial for maintaining protein folding integrity.

• Folding and Trafficking:

  • Ideally, proteins successfully fold and are trafficked to their designated cellular locations post-ER.

  • Enzymes that cleave carbohydrates influence protein-chaperone interactions, allowing for continued association with chaperones until proper folding occurs.

• Challenges in Folding:

  • If folding fails, additional carbohydrate cleavage events occur, contributing to improper protein structures.

  • Proteins are tagged with ubiquitin through an enzymatic cascade involving E1, E2, and E3 ligases, ultimately leading to their retro-translocation to the cytosol for degradation.

Role of Chaperones in Misfolded Proteins

• Recognizing Misfolding:

  • Misfolded proteins engage with chaperones such as BiP and HSP40 to assist in attempted refolding.

  • Misfolded proteins remain in the ER until recognized by the ubiquitin ligase mechanism for degradation.

Unfolded Protein Response (UPR)

• UPR Overview:

  • Triggered during periods of excessive misfolded proteins in the ER.

  • PERK Pathway:

    • Inhibits translation initiation and elongation, addressing the need for cellular homeostasis.

    • Effects on cell health if prolonged, specifically concerning mitochondrial protein translation.

• Differential Control for Mitochondrial Proteins:

  • Recent studies suggest separate regulatory mechanisms exist for mitochondrial-encoded proteins during UPR.

  • Communication between ER and mitochondria occurs at contact sites called MERCs, critical for maintaining cellular function.

• Research Context:

  • Ongoing research is vital for understanding the complex biology surrounding UPR and its implications for cellular health and disease.

  • The unfolding mechanisms and their interactions with organelles remain an active area of discovery.