negative regulation of formation of translation preinitiation complex

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of formation of translation preinitiation complex. [GOC:TermGenie]

The formation of the translation preinitiation complex (PIC) is a crucial step in the initiation of protein synthesis. This complex consists of the 40S ribosomal subunit, the initiator tRNA (Met-tRNAi), and several initiation factors (eIFs), including eIF1, eIF1A, eIF2, eIF3, eIF4A, eIF4B, eIF4E, and eIF4G. Negative regulation of PIC formation involves mechanisms that inhibit or suppress the assembly of this complex, thereby controlling the rate of protein translation.

One important regulatory mechanism involves the phosphorylation of eIF2α. The phosphorylation of eIF2α by kinases such as GCN2, PKR, and PERK leads to the inactivation of eIF2. Inactivated eIF2 is unable to bind to GTP and Met-tRNAi, thus preventing the recruitment of the initiator tRNA to the 40S ribosomal subunit. This inhibition of eIF2 activity significantly reduces the formation of the PIC and subsequently decreases protein translation.

Another regulatory mechanism involves the interaction of microRNAs (miRNAs) with mRNA transcripts. miRNAs are small non-coding RNAs that can bind to specific target mRNAs, leading to their degradation or translation repression. Some miRNAs target the mRNAs encoding translation initiation factors, such as eIF4E and eIF4G, thereby reducing the availability of these factors for PIC formation.

Moreover, the availability of mRNA cap-binding proteins, such as eIF4E, can be regulated by various cellular signaling pathways. For instance, during stress conditions, the phosphorylation of eIF4E by kinases such as MNK1 and MNK2 can inhibit its binding to the mRNA 5' cap, thereby reducing the recruitment of the 40S ribosomal subunit and hindering PIC assembly.

In addition to these mechanisms, the presence of cellular proteins that can interact with and inhibit the activity of eIFs can also negatively regulate PIC formation. For example, the protein 4E-BP1 can bind to eIF4E and prevent its interaction with the mRNA 5' cap, thereby inhibiting translation initiation.

The negative regulation of PIC formation is essential for maintaining cellular homeostasis. By controlling the rate of protein synthesis, these regulatory mechanisms ensure that cells can adapt to changes in environmental conditions, stress responses, and developmental cues. The fine-tuned control of translation initiation through negative regulation of PIC formation contributes to the precise regulation of gene expression and the overall cellular function.'
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Proteins (1)

Compounds (2)