Initiation factor

Last updated May 10, 2024

In molecular biology, initiation factors are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis.^[1]

Initiation factors can interact with repressors to slow down or prevent translation. They have the ability to interact with activators to help them start or increase the rate of translation. In bacteria, they are simply called IFs (i.e.., IF1, IF2, & IF3) and in eukaryotes they are known as eIFs (i.e.., eIF1, eIF2, eIF3).^[1] Translation initiation is sometimes described as three step process which initiation factors help to carry out. First, the tRNA carrying a methionine amino acid binds to the small subunit of ribosome, then binds to the mRNA, and finally joins together with the large subunit of ribosome. The initiation factors that help with this process each have different roles and structures.^[2]

Types

The initiation factors are divided into three major groups by taxonomic domains. There are some homologies shared (click the domain names to see the domain-specific factors):^[3]

InterPro	Bacterial	Archaeal	Eukaryotic	Common function^[3]
IPR006196	IF-1	aIF1A	eIF1A	diverse across domains^[3]
IPR015760	IF-2	aIF5B	eIF5B	diverse across domains^[3]
IPR001950 (SUI1)	YciH?	aIF1	eIF1	mRNA binding, fidelity of start codon^[3]
IPR001288	IF-3	—	—	fidelity of start codon^[4]
IPR001884	EF-P	aIF5A	eIF5A	an elongation factor^[5]
(three subunits)	—	aIF2	eIF2	binds tRNA_i^Met^[3]
IPR002769	—	aIF6	eIF6	keeps two ribosomal subunits disassociated by binding large subunit^[6]^[3]

Structure and function

Many structural domains have been conserved through evolution, as prokaryotic initiation factors share similar structures with eukaryotic factors.^[2] The prokaryotic initiation factor, IF3, assists with start site specificity, as well as mRNA binding.^[2]^[3] This is in comparison with the eukaryotic initiation factor, eIF1, who also performs these functions. The elF1 structure is similar to the C-terminal domain of IF3, as they each contain a five-stranded beta sheet against two alpha helices.^[2]

The prokaryotic initiation factors IF1 and IF2 are also homologs of the eukaryotic initiation factors eIF1A and eIF5B. IF1 and eIF1A, both containing an OB-fold, bind to the A site and assist in the assembly of initiation complexes at the start codon. IF2 and eIF5B assist in the joining of the small and large ribosomal subunits. The eIF5B factor also contains elongation factors. Domain IV of eIF5B is closely related to the C-terminal domain of IF2, as they both consist of a beta-barrel. The elF5B also contains a GTP-binding domain, which can switch from an active GTP to an inactive GDP. This switch helps to regulate the affinity of the ribosome for the initiation factor.^[2]

The bacterial 30S initiation complex, also showing the Shine-Dalgarno sequence upstream of the start codon TranslationInitiationBacteria.png — The bacterial 30S initiation complex, also showing the Shine-Dalgarno sequence upstream of the start codon

A eukaryotic initiation factor eIF3 plays an important role in translational initiation. It has a complex structure, composed of 13 subunits. It helps to create the 43S pre-initiation complex, composed of the small 40S subunit attached to other initiation factors. It also helps to create the 48S pre-initiation complex, consisting of the 43S complex with the mRNA. The eIF3 factor can also be used post-translation in order to separate the ribosomal complex and keep the small and large subunits apart. The initiation factor interacts with the eIF1 and eIF5 factors used for scanning and selection of the start codons. This can create changes in the selection of the factors, binding to different codons.^[8]

Another important eukaryotic initiation factor, eIF2, binds the tRNA containing methionine to the P site of the small ribosome. The P site is where the tRNA carrying an amino acid forms a peptide bond with the incoming amino acids and carries the peptide chain. The factor consists of an alpha, beta, and gamma subunit. The eIF2 gamma subunit is characterized by a GTP-binding domain and beta-barrel folds. It binds to the tRNA through GTP. Once the initiation factor helps the tRNA bind, the GTP hydrolyzes and is released the eIF2. The eIF2 beta subunit is identified by its Zn-finger. The eIF2 alpha subunit is characterized by an OB-fold domain and two beta strands. This subunit helps to regulate translation, as it becomes phosphorylated to inhibit protein synthesis.^[2]

The eIF4F complex supports the cap-dependent translation initiation process and is composed of the initiation factors eIF4A, eIF4E, and eIF4G. The cap end of the mRNA, being the 5’ end, is brought to the complex where the 43S ribosomal complex can bind and scan the mRNA for the start codon. During this process, the 60S ribosomal subunit binds and the large 80S ribosomal complex is formed. The eIF4G plays a role, as it interacts with the polyA-binding protein, attracting the mRNA. The eIF4E then binds the cap of the mRNA and the small ribosomal subunit binds to the eIF4G to begin the process of creating the 80S ribosomal complex. The eIF4A works to make this process more successful, as it is a DEAD box helicase. It allows for the unwinding of the untranslated regions of the mRNA to allow for ribosomal binding and scanning.^[9]

In cancer

In cancerous cells, initiation factors assist in cellular transformation and development of tumors. The survival and growth of cancer is directly related to the modification of initiation factors and is used as a target for pharmaceuticals. Cells need increased energy when cancerous and derive this energy from proteins. Over-expression of initiation factors correlates with cancers, as they increase protein synthesis for proteins needed in cancers. Some initiation factors, such as eIF4E, are important in synthesizing specific proteins needed for the proliferation and survival of cancer.^[10] The careful selection of proteins ensures that proteins that are usually limited in translation and only proteins needed for cancer cell growth will be synthesized. This includes proteins involved in growth, malignancy, and angiogenesis.^[8] The eIF4E factor, along with eIF4A and eIF4G, also play a role in transitioning benign cancer cells to metastatic.^[10]

The largest initiation factor, eIF3, is another significant initiation factor in human cancers. Due to its role in creating the 43S pre-initiation complex, it helps to bind the ribosomal subunit to the mRNA. The initiation factor has been linked to cancers through over-expression. For example, one of the thirteen eIF3 proteins, eIF3c, interacts with and represses proteins used in tumor suppression. Limited expression of certain eIF3 proteins, such as eIF3a an eIF3d, has been proven to decrease the vigorous growth of cancer cells.^[10] The over-expression of eIF3a has been linked to breast, lung, cervix, esophagus, stomach, and colon cancers. It is prevalent during early stages of oncogenesis and likely selectively translates proteins needed for cell proliferation.^[8] When eIF3a is suppressed, it has shown to decrease the malignancy of breast and lung cancer, most likely due to its role in tumor growth.^[10]

Related Research Articles

An internal ribosome entry site, abbreviated IRES, is an RNA element that allows for translation initiation in a cap-independent manner, as part of the greater process of protein synthesis. Initiation of eukaryotic translation nearly always occurs at and is dependent on the 5' cap of mRNA molecules, where the translation initiation complex forms and ribosomes engage the mRNA. IRES elements, however allow ribosomes to engage the mRNA and begin translation independently of the 5' cap.

Bacterial translation is the process by which messenger RNA is translated into proteins in bacteria.

Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: initiation, elongation, termination, and recapping.

Eukaryotic initiation factors (eIFs) are proteins or protein complexes involved in the initiation phase of eukaryotic translation. These proteins help stabilize the formation of ribosomal preinitiation complexes around the start codon and are an important input for post-transcription gene regulation. Several initiation factors form a complex with the small 40S ribosomal subunit and Met-tRNA_i^Met called the 43S preinitiation complex. Additional factors of the eIF4F complex recruit the 43S PIC to the five-prime cap structure of the mRNA, from which the 43S particle scans 5'-->3' along the mRNA to reach an AUG start codon. Recognition of the start codon by the Met-tRNA_i^Met promotes gated phosphate and eIF1 release to form the 48S preinitiation complex, followed by large 60S ribosomal subunit recruitment to form the 80S ribosome. There exist many more eukaryotic initiation factors than prokaryotic initiation factors, reflecting the greater biological complexity of eukaryotic translation. There are at least twelve eukaryotic initiation factors, composed of many more polypeptides, and these are described below.

A bacterial initiation factor (IF) is a protein that stabilizes the initiation complex for polypeptide translation.

<span class="mw-page-title-main">4EGI-1</span> Chemical compound

4EGI-1 is a synthetic chemical compound which has been found to interfere with the growth of certain types of cancer cells in vitro. Its mechanism of action involves interruption of the binding of cellular initiation factor proteins involved in the translation of transcribed mRNA at the ribosome. The inhibition of these initiation factors prevents the initiation and translation of many proteins whose functions are essential to the rapid growth and proliferation of cancer cells.

<span class="mw-page-title-main">Hepatitis C virus internal ribosome entry site</span>

The Hepatitis C virus internal ribosome entry site, or HCV IRES, is an RNA structure within the 5'UTR of the HCV genome that mediates cap-independent translation initiation.

<span class="mw-page-title-main">Nuclear cap-binding protein complex</span> RNA-binding protein

Nuclear cap-binding protein complex is a RNA-binding protein which binds to the 5' cap of pre-mRNA. The cap and nuclear cap-binding protein have many functions in mRNA biogenesis including splicing, 3'-end formation by stabilizing the interaction of the 3'-end processing machinery, nuclear export and protection of the transcripts from nuclease degradation. During mRNA export, the nuclear cap-binding protein complex recruits ribosomes to begin the pioneer round of translation. When RNA is exported to the cytoplasm the nuclear cap-binding protein complex is replaced by cytoplasmic cap binding complex. The nuclear cap-binding complex is a functional heterodimer and composed of Cbc1/Cbc2 in yeast and CBP20/CBP80 in multicellular eukaryotes. Human nuclear cap-binding protein complex shows the large subunit, CBP80 consists of 757 amino acid residues. Its secondary structure contains approximately sixty percent of helical and one percent of beta sheet in the strand. The small subunit, CBP20 has 98 amino acid residues. Its secondary structure contains approximately twenty percent of helical and twenty-four percent of beta sheet in the strand. Human nuclear cap-binding protein complex plays important role in the maturation of pre-mRNA and in uracil-rich small nuclear RNA.

Eukaryotic initiation factor 4A-I is a 46 kDa cytosolic protein that, in humans, is encoded by the EIF4A1 gene, which is located on chromosome 17. It is the most prevalent member of the eIF4A family of ATP-dependant RNA helicases, and plays a critical role in the initiation of cap-dependent eukaryotic protein translation as a component of the eIF4F translation initiation complex. eIF4A1 unwinds the secondary structure of RNA within the 5'-UTR of mRNA, a critical step necessary for the recruitment of the 43S preinitiation complex, and thus the translation of protein in eukaryotes. It was first characterized in 1982 by Grifo, et al., who purified it from rabbit reticulocyte lysate.

Eukaryotic translation initiation factor 1A, X-chromosomal (eIF1A) is a protein that in humans is encoded by the EIF1AX gene. This gene encodes an essential eukaryotic translation initiation factor. The protein is a component of the 43S pre-initiation complex (PIC), which mediates the recruitment of the small 40S ribosomal subunit to the 5' cap of messenger RNAs.

Eukaryotic translation initiation factor 5B is a protein that in humans is encoded by the EIF5B gene.

<span class="mw-page-title-main">EIF1</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 1 (eIF1) is a protein that in humans is encoded by the EIF1 gene. It is related to yeast SUI1.

Eukaryotic translation initiation factor 4 G (eIF4G) is a protein involved in eukaryotic translation initiation and is a component of the eIF4F cap-binding complex. Orthologs of eIF4G have been studied in multiple species, including humans, yeast, and wheat. However, eIF4G is exclusively found in domain Eukarya, and not in domains Bacteria or Archaea, which do not have capped mRNA. As such, eIF4G structure and function may vary between species, although the human EIF4G1 has been the focus of extensive studies.

Eukaryotic Initiation Factor 2 (eIF2) is an eukaryotic initiation factor. It is required for most forms of eukaryotic translation initiation. eIF2 mediates the binding of tRNA_i^Met to the ribosome in a GTP-dependent manner. eIF2 is a heterotrimer consisting of an alpha, a beta, and a gamma subunit.

The eukaryotic initiation factor-4A (eIF4A) family consists of 3 closely related proteins EIF4A1, EIF4A2, and EIF4A3. These factors are required for the binding of mRNA to 40S ribosomal subunits. In addition these proteins are helicases that function to unwind double-stranded RNA.

Translational regulation refers to the control of the levels of protein synthesized from its mRNA. This regulation is vastly important to the cellular response to stressors, growth cues, and differentiation. In comparison to transcriptional regulation, it results in much more immediate cellular adjustment through direct regulation of protein concentration. The corresponding mechanisms are primarily targeted on the control of ribosome recruitment on the initiation codon, but can also involve modulation of peptide elongation, termination of protein synthesis, or ribosome biogenesis. While these general concepts are widely conserved, some of the finer details in this sort of regulation have been proven to differ between prokaryotic and eukaryotic organisms.

Eukaryotic initiation factor 3 (eIF3) is a multiprotein complex that functions during the initiation phase of eukaryotic translation. It is essential for most forms of cap-dependent and cap-independent translation initiation. In humans, eIF3 consists of 13 nonidentical subunits (eIF3a-m) with a combined molecular weight of ~800 kDa, making it the largest translation initiation factor. The eIF3 complex is broadly conserved across eukaryotes, but the conservation of individual subunits varies across organisms. For instance, while most mammalian eIF3 complexes are composed of 13 subunits, budding yeast's eIF3 has only six subunits.

Eukaryotic initiation factor 4F (eIF4F) is a heterotrimeric protein complex that binds the 5' cap of messenger RNAs (mRNAs) to promote eukaryotic translation initiation. The eIF4F complex is composed of three non-identical subunits: the DEAD-box RNA helicase eIF4A, the cap-binding protein eIF4E, and the large "scaffold" protein eIF4G. The mammalian eIF4F complex was first described in 1983, and has been a major area of study into the molecular mechanisms of cap-dependent translation initiation ever since.

The 43S preinitiation complex is a ribonucleoprotein complex that exists during an early step of eukaryotic translation initiation. The 43S PIC contains the small ribosomal subunit (40S) bound by the initiation factors eIF1, eIF1A, eIF3, and the eIF2-Met-tRNA_i^Met-GTP ternary complex (eIF2-TC).

Archaeal initiation factors are proteins that are used during the translation step of protein synthesis in archaea. The principal functions these proteins perform include ribosome RNA/mRNA recognition, delivery of the initiator Met-tRNA_i^Met, methionine bound tRNAi, to the 40s ribosome, and proofreading of the initiation complex.

References

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1 2 3 4 5 6 Sonenberg N, Dever TE (February 2003). "Eukaryotic translation initiation factors and regulators". Current Opinion in Structural Biology. 13 (1): 56–63. doi:10.1016/S0959-440X(03)00009-5. PMID 12581660.
1 2 3 4 5 6 7 8 Benelli D, Londei P (January 2011). "Translation initiation in Archaea: conserved and domain-specific features". Biochemical Society Transactions. 39 (1): 89–93. doi:10.1042/BST0390089. PMID 21265752.
↑ Hussain T, Llácer JL, Wimberly BT, Kieft JS, Ramakrishnan V (September 2016). "Large-Scale Movements of IF3 and tRNA during Bacterial Translation Initiation". Cell. 167 (1): 133–144.e13. doi:10.1016/j.cell.2016.08.074. PMC 5037330 . PMID 27662086.
↑ Rossi D, Kuroshu R, Zanelli CF, Valentini SR (2013). "eIF5A and EF-P: two unique translation factors are now traveling the same road". Wiley Interdisciplinary Reviews. RNA. 5 (2): 209–22. doi:10.1002/wrna.1211. PMID 24402910. S2CID 25447826.
↑ Brina D, Grosso S, Miluzio A, Biffo S (October 2011). "Translational control by 80S formation and 60S availability: the central role of eIF6, a rate limiting factor in cell cycle progression and tumorigenesis". Cell Cycle. 10 (20): 3441–6. doi: 10.4161/cc.10.20.17796 . PMID 22031223.
↑ Gualerzi CO, Pon CL. "Initiation of mRNA translation in bacteria: structural and dynamic aspects". Cellular and Molecular Life Sciences. 72 (22): 4341–4367. doi: 10.1007/s00018-015-2010-3 . PMC 4611024 . PMID 26259514.
1 2 3 Dong Z, Zhang JT (September 2006). "Initiation factor eIF3 and regulation of mRNA translation, cell growth, and cancer". Critical Reviews in Oncology/Hematology. 59 (3): 169–80. doi:10.1016/j.critrevonc.2006.03.005. PMID 16829125.
↑ Montero H, Pérez-Gil G, Sampieri CL (June 2019). "Eukaryotic initiation factor 4A (eIF4A) during viral infections". Virus Genes. 55 (3): 267–273. doi:10.1007/s11262-019-01641-7. PMC 7088766 . PMID 30796742.
1 2 3 4 de la Parra C, Walters BA, Geter P, Schneider RJ (February 2018). "Translation initiation factors and their relevance in cancer". Current Opinion in Genetics & Development. 48: 82–88. doi:10.1016/j.gde.2017.11.001. PMC 7269109 . PMID 29153484.

External links

Initiation+Factor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)