Fundamentals of Molecular Biology - V.I. Rezyapkin 2009

Regulation of Gene Expression
Regulation of Gene Expression at the Translational Level

There are three main ways to regulate Translation:

✵ positive translational regulation (mRNA discrimination), based on the affinity of mRNA for Ribosomes and Translation initiation factors;

✵ negative regulation (translational repression), mediated by repressor Proteins that bind to mRNA and block translation initiation;

✵ global regulation, which regulates the Introduction/27.html">Translation of the entire pool of mRNA.

Positive Translational Regulation (mRNA Discrimination)

In prokaryotic mRNAs, efficient translation requires the initiation codon to be located at the apex of a hairpin Structure. It must be preceded, approximately 3–10 NUCLEOTIDES upstream, by the Shine-Dalgarno sequence, which is complementary to rRNA and ensures ribosome binding in the vicinity of the initiation codon (Fig. 8.25).

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Fig. 8.25. In prokaryotic mRNA, the initiation codon is located at the apex of a hairpin structure, preceded 3–10 nucleotides upstream by the Shine-Dalgarno sequence.

In eukaryotes, initiation typically occurs at the first AUG codon, provided it is in an optimal sequence context. Initiation efficiency depends on the Nucleotide Composition of the sequences flanking the initiation codon. The optimal sequence context for translation initiation in mammals is:

where the initiation codon is underlined, and essential nucleotides for initiation are shown in bold. If the first AUG is not in an optimal context, initiation starts from the next downstream AUG. The presence of a 5'-cap and a 3'-poly(A) tail is also crucial for translation initiation. In some eukaryotic mRNAs, translation initiation is driven by the recognition of an internal AUG. This requires an extended mRNA sequence that is recognized by specific proteins to facilitate initiation at the internal codon.

The initiation frequency and translation rate can vary significantly among different mRNAs. In prokaryotes, ribosome binding efficiency depends on the Organization OF THE ribosome-binding sites on the mRNA. The higher the affinity of these sites for the ribosome, the more efficiently translation is initiated. Accordingly, mRNAs are classified as "strong" or "weak" (Fig. 8.26). Initiation occurs frequently on "strong" mRNAs, where ribosomes are densely packed, resulting in the synthesis of large amounts of protein. On "weak" mRNAs, initiation is less frequent, and ribosomes are spaced far apart, leading to less intensive Protein Synthesis compared to "strong" mRNAs.

Fig. 8.26. Protein synthesis is much more intensive on "strong" mRNAs than on "weak" mRNAs.

Eukaryotic mRNAs are also categorized as "weak" or "strong"; the efficiency of translation initiation in these mRNAs is determined by the varying affinity of initiation factors for the 5'-terminal structures of the mRNA. The strength of an mRNA dictates the protein Abundance within The Cell. Proteins required in large amounts are encoded by "strong" mRNAs, whereas those needed in small quantities are encoded by "weak" mRNAs.

In prokaryotes, many mRNAs contain multiple cistrons. Ribosomes can initiate Cistron translation in several different ways. In some cases, ribosomes translate cistrons independently of one another (Fig. 8.27A). In other cases, initiation of an internal cistron occurs only after translation of the preceding cistron has begun (Fig. 8.27B). In a third mechanism, translation of an internal cistron is possible only after the translation of the preceding cistron is completed. Here, the large ribosomal subunit dissociates at the junction between the two cistrons, while the small subunit migrates to the next cistron to mediate the initiation of its translation (Fig. 8.27C).

Fig. 8.27. Mechanisms of translation of polycistronic prokaryotic mRNA. A — independent translation of cistrons; B — initiation of internal cistron translation occurs only after translation of the preceding cistron has started; C — translation of an internal cistron is possible only after completion of the preceding cistron's translation, with the large ribosomal subunit dissociating at the cistron boundary and the small subunit migrating to the next cistron.

Negative Translational Regulation (Translational Repression)

Negative regulation is mediated by repressor proteins that bind to mRNA. Often, an unstable hairpin is located at the binding site. The repressor protein stabilizes this hairpin, thereby preventing either the interaction of the ribosome with the mRNA (Fig. 8.28A) or the progression of the ribosome along the mRNA (Fig. 8.28B). In some cases, the repressor is a protein encoded by the mRNA itself.

Fig. 8.28. Negative regulation of translation. A — the repressor stabilizes the hairpin, preventing the ribosome from interacting with the mRNA. B — the repressor stabilizes the hairpin, blocking the movement of the ribosome along the mRNA.

Let us consider The regulation of ferritin synthesis as an example (Fig. 8.29). This protein binds excess free iron in the cell, and its levels depend on the concentration of iron ions. In the presence of iron, ferritin is synthesized, whereas in its deficiency, the protein is not produced because the translation of ferritin mRNA is blocked. Ferritin mRNA Translation relies on a repressor protein that, in the absence of iron, binds to a sequence forming a hairpin structure at the 5'-end of the mRNA. This binding stabilizes the hairpin and represses translation at the initiation stage. In the presence of iron ions, the repressor forms a complex with them, thereby losing its affinity for the mRNA. Upon dissociation of the repressor, the mRNA becomes translatable, leading to the accumulation of ferritin in the cell. The resulting increase in ferritin levels binds the iron and lowers the concentration of free iron in the cell. As a consequence, the repressor-iron complex dissociates, the repressor regains its affinity for the mRNA, and by binding to it, blocks its translation once again.

Fig. 8.29. Regulation of ferritin synthesis