negative regulation of translational initiation

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate or extent of translational initiation. [GOC:go_curators]

Negative regulation of translational initiation is a critical cellular process that controls the expression of genes by modulating the rate at which proteins are synthesized. This intricate process involves a series of molecular events that suppress the initiation of protein synthesis, preventing the formation of functional ribosomes on messenger RNA (mRNA). Here’s a detailed description:

**1. Initiation Complex Formation:**
* The initiation of translation begins with the assembly of an initiation complex, comprising the small ribosomal subunit (40S), the initiator methionine tRNA (Met-tRNAi), and initiation factors (eIFs).
* These factors, such as eIF1, eIF1A, and eIF3, facilitate the recruitment of the small ribosomal subunit to the 5' cap of mRNA.

**2. Scanning for the Start Codon:**
* Once bound to the mRNA, the 40S subunit, guided by eIF4F, scans the mRNA in a 5' to 3' direction in search of the AUG start codon, which signals the beginning of the protein-coding region.

**3. Recognition of the Start Codon:**
* Upon encountering the AUG codon, the initiator tRNA (Met-tRNAi) base pairs with the codon, bringing the methionine amino acid into position for protein synthesis.
* This recognition step involves the participation of eIF2, which delivers Met-tRNAi to the 40S subunit.

**4. Recruitment of the Large Subunit:**
* The binding of Met-tRNAi to the start codon triggers the recruitment of the large ribosomal subunit (60S) to the initiation complex, forming a functional ribosome.

**5. Negative Regulation Mechanisms:**
* **a. Inhibition of eIF2 Activity:**
* The phosphorylation of eIF2α, a subunit of eIF2, by various kinases (e.g., PERK, GCN2, PKR) inactivates eIF2.
* Phosphorylated eIF2 binds tightly to eIF2B, a guanine nucleotide exchange factor (GEF), preventing the exchange of GDP for GTP on eIF2.
* This inhibits the ability of eIF2 to deliver Met-tRNAi to the 40S subunit, thus suppressing initiation.
* **b. Inhibition of eIF4E Activity:**
* eIF4E, a component of eIF4F, binds to the 5' cap of mRNA, facilitating ribosome recruitment.
* Certain proteins, such as 4E-binding proteins (4E-BPs), can bind to eIF4E, blocking its interaction with the cap structure.
* This inhibition prevents the association of the 40S subunit with mRNA, hindering initiation.
* **c. mRNA Degradation:**
* In some cases, the mRNA itself can be targeted for degradation, preventing the initiation of translation.
* This can be mediated by microRNAs (miRNAs) or other regulatory mechanisms.

**6. Consequences of Negative Regulation:**
* Negative regulation of translational initiation plays a crucial role in cellular responses to stress, nutrient availability, and developmental cues.
* It ensures efficient allocation of resources by controlling the synthesis of proteins.
* For example, under conditions of stress, the phosphorylation of eIF2α inhibits the synthesis of general proteins while promoting the expression of specific stress-response proteins.

**7. Regulatory Complexity:**
* The negative regulation of translational initiation is a highly regulated and interconnected process involving a vast network of proteins and signaling pathways.
* It is influenced by various cellular factors, including environmental conditions, developmental stage, and cellular signaling events.'
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Proteins (5)

Compounds (107)