Regulating Protein Translation

Regulation of Translation without Changing RNA Levels

• The focus is on modulating protein expression via translation control, while keeping RNA levels unchanged.

Aconitase and Iron Metabolism

• Aconitase: A regulator of mRNA related to iron levels.
• Low Iron Levels: Aconitase binds, inhibiting ferritin translation, preventing iron storage.
• High Iron Levels: Aconitase is released, allowing translation of ferritin mRNA, increasing iron storage.
• This binding can have opposing effects on different mRNAs, demonstrating the complexity of gene regulation in iron metabolism.

Riboswitches

• Definition: Regulatory RNA structures that control translation based on ligand binding without the need for proteins.

• Mechanism: Small molecules bind to riboswitches, altering their conformation and either permitting or blocking translation.

• Example: An RNA with multiple hairpins can rearrange its structure to block the translation start site (AUG).

Translational Initiation Factors

• EIF2 (Eukaryotic Initiation Factor 2): Key factor necessary for the assembly of the ribosome at the mRNA's 5' end.
• Phosphorylation of EIF2:
  • It inhibits EIF2 by trapping it in its GDP-bound state, hindering its ability to bind GTP.
  • The inactivation of EIF2 restricts the formation of the initiation complex and can lead to global downregulation of translation.
• Conditions Leading to EIF2 Phosphorylation:
  • Starvation: Reduces translation to conserve amino acids.
  • Viral Infection: Prevents viral replication by downregulating translation.

Global Downregulation and Stress Responses

• Global Translation Shutdown: The cell reduces overall translation rates while selectively upregulating specific genes that respond to stressors.
• Mechanisms of Selective Upregulation:
  • Open Reading Frames (ORFs): Genes often have upstream shorter ORFs preventing ribosomes from reaching the main coding sequence under normal conditions.
  • When EIF2 is phosphorylated, translation of these shorter ORFs fails, allowing ribosomes to reach and translate the main ORF necessary for a stress response (e.g., immune response, amino acid transport).

Proteolysis and Gene Regulation

• Proteolytic Pathways: Proteases cleave peptide bonds spontaneously through lowering activation energy, using ATP for regulatory mechanisms.
• Regulatory Proteolysis: Specific proteins are targeted for degradation to control gene expression patterns within the cell.

Epigenetic Inheritance

• Definition: Heritable changes in gene expression patterns that do not involve alterations in the DNA sequence.
• Example: Different cell types like macrophages and neurons have identical DNA yet express genes differently, demonstrating epigenetic regulation.

Positive Feedback Loops in Gene Expression

• A gene can regulate its expression once activated, leading to stable and heritable patterns of expression. This ensures that once a gene is turned on, it can maintain that expression without external regulatory input.

Protein Transport Mechanisms

• Importance of Sequence: Proteins contain specific sequences necessary for transport across membranes, embedded within their primary structure, influenced by their secondary and tertiary structures.

• Overview of Protein Transport: Discusses three forms of protein transport across cellular compartments, highlighting the significance of conserved sequences in protein targeting and function.