eIF2B In Regulation of Protein Synthesis

Original Text: eIF2B In Regulation of Protein Synthesis

In eukaryotic protein synthesis, translation is a important process to organize free amino acid into ploypeptide from mRNA codes. In this process, Eukaryotic initiation factor 2B (eIF2B) is involved a key regylatory role in translation. However, this protein is highly regulated in different environmental stresses, such as starvation and insulin upregulation after food intake. As the result the protein synthesis is altered through the activation, inhibition and other alternation on eIF2B. In addition, the abnormal encoding of eIF2B protein leads to severe neurodegenerative diseases in children as CACH( chldhood ataxia with central nervous system hypomyelination)/VWM ( leukoencephalopathy with vanishing white matter) syndrome.(A. Fogli et al. 2006). In this paper, I will illustrate the regulation of protein synthesis mediated by eIF2B and the eIF2B mutation related diseases.

In translation, it is divided into 3 major processes, initiation, elongation and termination. Most regulatory mechanisms are taking part in initiation, including the eIF2B. Therefore we need to understand initation process and highlight the function of eIF2B. Initially, tralsation initiation requires 2 seperated parts of ribosomes, 40S and 60S subunits. These subunited are recyclied from previous translation and called post-termination ribosomal complex (post-TCs). Another key component, initiator tRNA( Met-tRNA) binds with a eukaryotic initiator factor family member, eIF2. This complex linked with a GTP to become a Ternary complex(TC). TC associates with the 40S subunit with other eukayotic initation factors, such as eIF3 and eIF1A to form a 43S preinitiation complex.

Meanwhile, the activation of mRNA is achieved by capping mechanism. As the natural 5’UTR is not able to located on 40S subunit. Therefore other eIF proteins assist this action- the involvement of eIF4F complex. It consists eIF4A, eIF4E and eIF4G (Pisarev t al,.2008). The interaction between eIF4E and eIF4G activate the starting site selection in translation of mRNA by binding to cap structure. This action enhances the helicase activty of eIF2A to bind the 7-methyl-GTP (m7GTP) region in the 5’ UTR of mRNA. Furthermore, eIF4F complex binds with poly(A) binding protein (PABA) and eIF4B to bridge the 3’end and 5’end of mRNA by circulate it. It generates a ribosomal binding site for 43S preinitiation complex to bind on. The enhanced eIF2A with high helicase activity promotes ribosomal attachment between mRNA with 43 preinitiation complex. The next process is called “scanning” (Kozak and Shatkin et al, 1978.). The ribosome moves along from 5’ to 3’ unsaturated end of mRNA to until the first AUG starting codon is detected. It allows the appopriate codon for Met-tRNA anticodon assoication. In this process, ATP will be hydrolysed for energy. Moreover, the recognition of AUG codon is still remain unclear but researhes supported the assistance of eIF2 is involved in the recognition. (Donahue et al., 1988.). After the recognition, initatior factor eIF5 initated the GTP hydrolysis because eIF5 is a GTP-ase activating protein to stimulate dissoication of eIF2-GDP, Pi and other eIF protein As the result the Met-tRNA is located on ribosomal P site and ready for translation elongation. The role of eIF2B involved in initiation is after the releasing of eIF2-GDP. It plays a recycling reaction by regenerating eIF2-GDP to eIF2-GTP as eIF2B is a Guanine nucleotide exchange factors (GEFs).

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Revised Text:

In eukaryotic protein synthesis, translation is an important process in organizing free amino acids into polypeptides from mRNA codes. In this process, eukaryotic initiation factor 2B (eIF2B) has a key regulatory role in translation. However, this protein is highly regulated in different environmental stresses, such as starvation and insulin upregulation after food intake. As a result, the protein synthesis is altered through the activation, inhibition and other alternation on eIF2B. In addition, the abnormal encoding of eIF2B protein leads to severe neuro-degenerative diseases in children such as CACH( chldhood ataxia with central nervous system hypomyelination), VWM (leukoencephalopathy with vanishing white matter) syndrome(A. Fogli et al. 2006). In this paper, I will illustrate the regulation of protein synthesis mediated by eIF2B and the eIF2B mutation related diseases.

Translation is divided into 3 major processes; initiation, elongation and termination. Most regulatory mechanisms take part in initiation, including the eIF2B. Therefore we need to understand the initiation process and highlight the function of eIF2B. Initially, translation initiation requires 2 separated parts of ribosomes, the 40S and 60S subunits. These sub-united are recycled from previous translation and are called post-termination ribosomal complexes (post-TCs). Another key component, the initiator tRNA( Met-tRNA) binds with a eukaryotic initiator factor family member, eIF2. This complex is linked with a GTP to become a Ternary complex(TC). TC associates with the 40S subunit with other eukayotic initiation factors, such as eIF3 and eIF1A to form a 43S pre-initiation complex.

Meanwhile, the activation of mRNA is achieved by a capping mechanism, as the natural 5’UTR is not able to locate on the 40S subunit. Therefore other eIF proteins assist this action, the involvement of eIF4F complex. It consists eIF4A, eIF4E and eIF4G (Pisarev t al,.2008). The interaction between eIF4E and eIF4G activates the starting site selection in translation of mRNA by binding to cap structure. This action enhances the helicase activity of eIF2A to bind the 7-methyl-GTP (m7GTP) region in the 5’ UTR of mRNA. Furthermore, the eIF4F complex binds with poly(A) binding protein (PABA) and eIF4B to bridge the 3’end and 5’end of mRNA by encircling it. It generates a ribosomal binding site for 43S pre-initiation complex to bind on. The enhanced eIF2A, with high helicase activity, promotes ribosomal attachment between mRNA with 43 preinitiation complex.

The next process is called “scanning” (Kozak and Shatkin et al, 1978.). The ribosome moves along from the 5’ to the 3’ unsaturated end of mRNA until the first AUG starting codon is detected. It allows the appropriate codon for Met-tRNA anti-codon association. In this process, ATP will be hydrolyzed for energy. The recognition of the AUG codon still remains unclear but research supports the assistance of eIF2 involvement in the recognition. (Donahue et al., 1988.). After the recognition, initiator factor eIF5 initiates the GTP hydrolysis (because eIF5 is a GTP-ase activating protein) to stimulate dissociation of eIF2-GDP, Pi and other eIF proteins. As a result, the Met-tRNA is located on the ribosomal P site and is ready for translation elongation. The role of eIF2B involved in initiation, is after the releasing of eIF2-GDP. It plays a recycling reaction by regenerating eIF2-GDP to eIF2-GTP, as eIF2B is a Guanine nucleotide exchange factor (GEF).

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