translation initiation

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  • Translation initiation
    • Aim is to recruit the small ribosomal subunit and an initiator tRNA charged with methionine to the mRNA molecule
      • AUG start codon needs to be found on the mRNA
    • process guided by translation initiation factors
      • IFs in prokaryotes and eIFs in eukaryotes
    • small 40S ribosomal subunit recruited via the 7-methylguanosine cap at the 5' end of mRNA
      • relies on a complex of initiation factors called eIF4F
        • eIF4E
        • eIF4A
        • eIF4G
        • eIF4E protein binds the 5' cap and locks the eIF4F complex onto the mRNA
          • 40S subunit recruited with the initiator tRNA
            • aided by
              • eIF2
              • eIF5B
            • this forms the 43S pre-initiation complex
              • 40S subunit and associated factors scan the 5'UTR to find the first start codon
                • eIF4A aids this
                  • RNA helicase that unwinds stem loop structures in the 5'UTR that otherwise impede translation initiation
                  • eIF4B required to activate eIF4A
                • PolyA tail stimulates translation by sending ribosomes which have just ended a round of transcription back to the 3' end for another
                  • uses the eIF4G subunit of eIF4F
                    • interacts with the polyA binding protein PAB2, causing the mRNA to form a closed loop structure, resulting in the closed-loop model of transcription
    • occurs in the cytoplasm as intracellular mechanisms prevent mRNAs from interacting with ribosomal subunits inside the nulceus
      • this prevents 80S formation
      • non-ribosomal association factors (NAFs) also prevent 80S formation in nucleus
      • pre-40S rRNA is not fully processed as it has a pre-20S rRNA component which needs to be cleaved to an 18S component
      • However, recent studies showed that many ribosomal proteins, rRNAs and TFs associate with nascent transcripts in the nucleus
        • study has also found that radioactive AAs are incorporated at chromosomes of polytenic nuclei.
        • a recent study by al-jubran also found that 80s ribosomes are present in the nucleus
    • Non-AUG start codons
      • translation can be initiated from a non-AUG start codon in proks and euks
        • in euks these start from CUG and UUG
          • e.g. the FGF-2 growth factor gene can start translation from typical AUG but also from 3 separate CUG codons where the initiator tRNA is charged with leucine
            • these resultant isoforms of the FGF-2 protein have differing physiological properties and induce expression of different genes
          • examples of a group of alternative translation start sites called INTERNAL RIBOSOME ENTRY SITES
            • also present in prok polycistronic mRNAs so that the ribosome can bypass the most upstream AUG and instead initiate transcription at a downstream AUG start codon
            • not confined to viruses
              • in euks associated with stress and mitosis
                • in mitosis, cells dephosphorylate eIF4E, reducing its affinity for the 5'-cap
                  • causes the translation machinery to preferentially translate from IRES sequences
                • IRES-containing mRNAs allow for translation also when regular translational pathways become unavailable due to viral infection
                  • some viruses operate by shutting down the host cell translation by destroying the euk initiation factor eIF4G, preventing the interaction between the 5'cap and polyA tail - closed-loop structure cannot form
                    • the viral mRNAs then take over the translation machinery using their IRES sequences
        • very rare

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