Prokaryotes In
bacteria, the initiation of translation occurs when
IF-3, along with the
30S ribosomal subunit, bind to the Shine–Dalgarno (SD) sequence of the 5′ UTR. Some mRNAs are leaderless. In both domains, genes without Shine–Dalgarno sequences are also translated in a less understood manner. A requirement seems to be a lack of secondary structure near the initiation codon.
Eukaryotes Pre-initiation complex regulation The regulation of translation in eukaryotes is more complex than in prokaryotes. Initially, the
eIF4F complex is recruited to the
5′ cap, which in turn recruits the ribosomal complex to the 5′ UTR. Both
eIF4E and
eIF4G bind the 5′ UTR, which limits the rate at which translational initiation can occur. However, this is not the only regulatory step of
translation that involves the 5′ UTR.
RNA-binding proteins sometimes serve to prevent the pre-initiation complex from forming. An example is regulation of the
msl2 gene. The protein SXL attaches to an intron segment located within the 5′ UTR segment of the primary transcript, which leads to the inclusion of the intron after processing. This sequence allows the recruitment of proteins that bind simultaneously to both the 5′ and
3′ UTR, not allowing translation proteins to assemble. However, it has also been noted that SXL can also repress translation of RNAs that do not contain a
poly(A) tail, or more generally, 3′ UTR.
Closed-loop regulation Another important regulator of translation is the interaction between 3′ UTR and the 5′ UTR. bound to the
3′UTR and 5′ UTR causing a circularization that regulates
translation The closed-loop structure inhibits translation. This has been observed in
Xenopus laevis, in which eIF4E bound to the 5′ cap interacts with Maskin bound to
CPEB on the 3′ UTR, creating translationally inactive
transcripts. This translational inhibition is lifted once CPEB is
phosphorylated, displacing the Maskin binding site, allowing for the
polymerization of the PolyA tail, which can recruit the translational machinery by means of
PABP. However, this mechanism has been under great scrutiny.
Ferritin regulation Iron levels in cells are maintained by translation regulation of many proteins involved in iron storage and metabolism. The 5′ UTR has the ability to form a hairpin loop secondary structure (known as the
iron response element or IRE) that is recognized by iron-regulatory proteins (IRP1 and IRP2). In low levels of iron, the ORF of the target mRNA is blocked as a result of
steric hindrance from the binding of IRP1 and IRP2 to the IRE. When iron is high, then the two iron-regulatory proteins do not bind as strongly and allow proteins to be expressed that have a role in iron concentration control. This function has gained some interest after it was revealed that the translation of
amyloid precursor protein may be disrupted due to a
single-nucleotide polymorphism to the IRE found in the 5′ UTR of its
mRNA, leading to a spontaneous increased risk of
Alzheimer's disease.
uORFs and reinitiation Another form of translational regulation in eukaryotes comes from unique elements on the 5′ UTR called upstream
open reading frames (uORF). These elements are fairly common, occurring in 35–49% of all human genes. A uORF is a coding sequence located in the 5′ UTR located upstream of the coding sequences initiation site. These uORFs contain their own initiation codon, known as an upstream AUG (uAUG). This
codon can be scanned for by ribosomes and then translated to create a product, which can regulate the translation of the main protein coding sequence or other uORFs that may exist on the same transcript. The translation of the protein within the main ORF after a uORF sequence has been translated is known as reinitiation. The process of reinitiation is known to reduce the translation of the ORF protein. Control of protein regulation is determined by the distance between the uORF and the first codon in the main ORF. The IRES enables the viral transcript to translate more efficiently due to the lack of needing a preinitiation complex, allowing the virus to replicate quickly. == Role in transcriptional regulation ==