Eukaryotic translation initiation (Homo sapiens)
From WikiPathways
Description
Initiation of translation in the majority of eukaryotic cellular mRNAs depends on the 5'-cap (m7GpppN) and involves ribosomal scanning of the 5' untranslated region (5'-UTR) for an initiating AUG start codon. Therefore, this mechanism is often called cap-dependent translation initiation. Proximity to the cap, as well as the nucleotides surrounding an AUG codon, influence the efficiency of the start site recognition during the scanning process. However, if the recognition site is poor enough, scanning ribosomal subunits will ignore and skip potential starting AUGs, a phenomenon called leaky scanning. Leaky scanning allows a single mRNA to encode several proteins that differ in their amino-termini. Merrick (2010) provides an overview of this process and hghlights several features of it that remain incompletely understood.
Several eukaryotic cell and viral mRNAs initiate translation by an alternative mechanism that involves internal initiation rather than ribosomal scanning. These mRNAs contain complex nucleotide sequences, called internal ribosomal entry sites, where ribosomes bind in a cap-independent manner and start translation at the closest downstream AUG codon.
Initiation on several viral and cellular mRNAs is cap-independent and is mediated by binding of the ribosome to internal ribosome entry site (IRES) elements. These elements are often found in characteristically long structured regions on the 5'-UTR of an mRNA that may or may not have regulatory upstream open reading frames (uORFs). Both of these features on the 5'-end of the mRNA hinder ribosomal scanning, and thus promote a cap-independent translation initiation mechanism. IRESs act as specific translational enhancers that allow translation initiation to occur in response to specific stimuli and under the control of different trans-acting factors, as for example when cap-dependent protein synthesis is shut off during viral infection. Such regulatory elements have been identified in the mRNAs of growth factors, protooncogenes, angiogenesis factors, and apoptosis regulators, which are translated under a variety of stress conditions, including hypoxia, serum deprivation, irradiation and apoptosis. Thus, cap-independent translational control might have evolved to regulate cellular responses in acute but transient stress conditions that would otherwise lead to cell death, while the same mechanism is of major importance for viral mRNAs to bypass the shutting-off of host protein synthesis after infection. Encephalomyocarditis virus (EMCV) and hepatitis C virus exemplify two distinct mechanisms of IRES-mediated initiation. In contrast to cap-dependent initiation, the eIF4A and eIF4G subunits of eIF4F bind immediately upstream of the EMCV initiation codon and promote binding of a 43S complex. Accordingly, EMCV initiation does not involve scanning and does not require eIF1, eIF1A, and the eIF4E subunit of eIF4F. Nonetheless, initiation on some EMCV-like IRESs requires additional non-canonical initiation factors, which alter IRES conformation and promote binding of eIF4A/eIF4G. Initiation on the hepatitis C virus IRES is simpler: a 43S complex containing only eIF2 and eIF3 binds directly to the initiation codon as a result of specific interaction of the IRES and the 40S subunit.
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- Pause A, Belsham GJ, Gingras AC, Donzé O, Lin TA, Lawrence JC, Sonenberg N.; ''Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function.''; PubMed Europe PMC Scholia
- Sampath P, Mazumder B, Seshadri V, Fox PL.; ''Transcript-selective translational silencing by gamma interferon is directed by a novel structural element in the ceruloplasmin mRNA 3' untranslated region.''; PubMed Europe PMC Scholia
- Pestova TV, Borukhov SI, Hellen CU.; ''Eukaryotic ribosomes require initiation factors 1 and 1A to locate initiation codons.''; PubMed Europe PMC Scholia
- Mazumder B, Sampath P, Seshadri V, Maitra RK, DiCorleto PE, Fox PL.; ''Regulated release of L13a from the 60S ribosomal subunit as a mechanism of transcript-specific translational control.''; PubMed Europe PMC Scholia
- Grifo JA, Tahara SM, Morgan MA, Shatkin AJ, Merrick WC.; ''New initiation factor activity required for globin mRNA translation.''; PubMed Europe PMC Scholia
- Safer B, Adams SL, Anderson WF, Merrick WC.; ''Binding of MET-TRNAf and GTP to homogeneous initiation factor MP.''; PubMed Europe PMC Scholia
- Pestova TV, Shatsky IN, Hellen CU.; ''Functional dissection of eukaryotic initiation factor 4F: the 4A subunit and the central domain of the 4G subunit are sufficient to mediate internal entry of 43S preinitiation complexes.''; PubMed Europe PMC Scholia
- Merrick WC.; ''Eukaryotic protein synthesis: still a mystery.''; PubMed Europe PMC Scholia
- Kozak M.; ''Evaluation of the "scanning model" for initiation of protein synthesis in eucaryotes.''; PubMed Europe PMC Scholia
- Chakrabarti A, Maitra U.; ''Function of eukaryotic initiation factor 5 in the formation of an 80 S ribosomal polypeptide chain initiation complex.''; PubMed Europe PMC Scholia
- Trachsel H, Erni B, Schreier MH, Staehelin T.; ''Initiation of mammalian protein synthesis. II. The assembly of the initiation complex with purified initiation factors.''; PubMed Europe PMC Scholia
- Rowlands AG, Panniers R, Henshaw EC.; ''The catalytic mechanism of guanine nucleotide exchange factor action and competitive inhibition by phosphorylated eukaryotic initiation factor 2.''; PubMed Europe PMC Scholia
- Iost I, Dreyfus M, Linder P.; ''Ded1p, a DEAD-box protein required for translation initiation in Saccharomyces cerevisiae, is an RNA helicase.''; PubMed Europe PMC Scholia
- Benne R, Hershey JW.; ''The mechanism of action of protein synthesis initiation factors from rabbit reticulocytes.''; PubMed Europe PMC Scholia
- Schreier MH, Erni B, Staehelin T.; ''Initiation of mammalian protein synthesis. I. Purification and characterization of seven initiation factors.''; PubMed Europe PMC Scholia
- Sonenberg N, Rupprecht KM, Hecht SM, Shatkin AJ.; ''Eukaryotic mRNA cap binding protein: purification by affinity chromatography on sepharose-coupled m7GDP.''; PubMed Europe PMC Scholia
- Dever TE, Wei CL, Benkowski LA, Browning K, Merrick WC, Hershey JW.; ''Determination of the amino acid sequence of rabbit, human, and wheat germ protein synthesis factor eIF-4C by cloning and chemical sequencing.''; PubMed Europe PMC Scholia
- Merrick WC, Kemper WM, Anderson WF.; ''Purification and characterization of homogeneous initiation factor M2A from rabbit reticulocytes.''; PubMed Europe PMC Scholia
- Asano K, Clayton J, Shalev A, Hinnebusch AG.; ''A multifactor complex of eukaryotic initiation factors, eIF1, eIF2, eIF3, eIF5, and initiator tRNA(Met) is an important translation initiation intermediate in vivo.''; PubMed Europe PMC Scholia
- Peterson DT, Merrick WC, Safer B.; ''Binding and release of radiolabeled eukaryotic initiation factors 2 and 3 during 80 S initiation complex formation.''; PubMed Europe PMC Scholia
- Goumans H, Thomas A, Verhoeven A, Voorma HO, Benne R.; ''The role of eIF-4C in protein synthesis initiation complex formation.''; PubMed Europe PMC Scholia
- Imataka H, Gradi A, Sonenberg N.; ''A newly identified N-terminal amino acid sequence of human eIF4G binds poly(A)-binding protein and functions in poly(A)-dependent translation.''; PubMed Europe PMC Scholia
- Chuang RY, Weaver PL, Liu Z, Chang TH.; ''Requirement of the DEAD-Box protein ded1p for messenger RNA translation.''; PubMed Europe PMC Scholia
- Lahn BT, Page DC.; ''Functional coherence of the human Y chromosome.''; PubMed Europe PMC Scholia
- Yoder-Hill J, Pause A, Sonenberg N, Merrick WC.; ''The p46 subunit of eukaryotic initiation factor (eIF)-4F exchanges with eIF-4A.''; PubMed Europe PMC Scholia
- Pestova TV, Lomakin IB, Lee JH, Choi SK, Dever TE, Hellen CU.; ''The joining of ribosomal subunits in eukaryotes requires eIF5B.''; PubMed Europe PMC Scholia
- Damoc E, Fraser CS, Zhou M, Videler H, Mayeur GL, Hershey JW, Doudna JA, Robinson CV, Leary JA.; ''Structural characterization of the human eukaryotic initiation factor 3 protein complex by mass spectrometry.''; PubMed Europe PMC Scholia
- Majumdar R, Bandyopadhyay A, Maitra U.; ''Mammalian translation initiation factor eIF1 functions with eIF1A and eIF3 in the formation of a stable 40 S preinitiation complex.''; PubMed Europe PMC Scholia
- Dholakia JN, Wahba AJ.; ''Mechanism of the nucleotide exchange reaction in eukaryotic polypeptide chain initiation. Characterization of the guanine nucleotide exchange factor as a GTP-binding protein.''; PubMed Europe PMC Scholia
History
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External references
DataNodes
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Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| 40S ribosomal complex | Arrow | R-HSA-72673 (Reactome)  | ||
| 40S ribosomal complex | R-HSA-72676 (Reactome) | |||
| 40S:Met-tRNAi:mRNA | Arrow | R-HSA-72619 (Reactome) | ||
| 40S:Met-tRNAi:mRNA | R-HSA-72672 (Reactome) | |||
| 40S:eIF3:eIF1A | Arrow | R-HSA-72676 (Reactome) | ||
| 40S:eIF3:eIF1A | R-HSA-72691 (Reactome) | |||
| 43S complex | Arrow | R-HSA-72691 (Reactome) | ||
| 43S complex | R-HSA-156808 (Reactome) | |||
| 43S complex | R-HSA-157849 (Reactome) | |||
| 43S:
Ceruloplasmin mRNA:eIF4F:eIF4B:eIF4H:PABP | Arrow | R-HSA-156808 (Reactome) | ||
| 43S:
Ceruloplasmin mRNA:eIF4F:eIF4B:eIF4H:PABP | R-HSA-156823 (Reactome) | |||
| 43S:mRNA:eIF4F:eIF4B:eIF4H | Arrow | R-HSA-157849 (Reactome) | ||
| 43S:mRNA:eIF4F:eIF4B:eIF4H | R-HSA-72621 (Reactome) | |||
| 48S complex | Arrow | R-HSA-72621 (Reactome) | ||
| 48S complex | Arrow | R-HSA-72697 (Reactome) | ||
| 48S complex | R-HSA-72619 (Reactome) | |||
| 48S complex | R-HSA-72697 (Reactome) | |||
| 60S ribosomal complex | Arrow | R-HSA-72673 (Reactome) | ||
| 60S ribosomal complex | R-HSA-156826 (Reactome) | |||
| 60S ribosomal complex | R-HSA-72672 (Reactome) | |||
| 60s ribosomal
complex lacking L13a subunit | Arrow | R-HSA-156826 (Reactome) | ||
| 80S ribosome | R-HSA-72673 (Reactome) | |||
| 80S:Met-tRNAi:mRNA:eIF5B:GTP | Arrow | R-HSA-72672 (Reactome) | ||
| 80S:Met-tRNAi:mRNA:eIF5B:GTP | R-HSA-72671 (Reactome) | |||
| 80S:Met-tRNAi:mRNA | Arrow | R-HSA-72671 (Reactome) | ||
| ADP | Arrow | R-HSA-72621 (Reactome) | ||
| ADP | Arrow | R-HSA-72647 (Reactome) | ||
| ATP | Arrow | R-HSA-72621 (Reactome) | ||
| ATP | R-HSA-72621 (Reactome) | |||
| ATP | R-HSA-72647 (Reactome) | |||
| Ceruloplasmin mRNA:eIF4F:eIF4B:eIF4H | R-HSA-156808 (Reactome) | |||
| EIF1AX | Arrow | R-HSA-156808 (Reactome) | ||
| EIF1AX | Arrow | R-HSA-157849 (Reactome) | ||
| EIF1AX | Arrow | R-HSA-72619 (Reactome) | ||
| EIF1AX | Arrow | R-HSA-72673 (Reactome) | ||
| EIF1AX | Arrow | R-HSA-72697 (Reactome) | ||
| EIF1AX | R-HSA-156808 (Reactome) | |||
| EIF1AX | R-HSA-157849 (Reactome) | |||
| EIF1AX | R-HSA-72673 (Reactome) | |||
| EIF1AX | R-HSA-72676 (Reactome) | |||
| EIF1AX | R-HSA-72697 (Reactome) | |||
| EIF2S1:EIF2S2:EIF2S3 | Arrow | R-HSA-72697 (Reactome) | ||
| EIF2S1:EIF2S2:EIF2S3 | R-HSA-72663 (Reactome) | |||
| EIF2S1:EIF2S2:EIF2S3 | R-HSA-72697 (Reactome) | |||
| EIF4B | Arrow | R-HSA-72619 (Reactome) | ||
| EIF4B | R-HSA-72647 (Reactome) | |||
| EIF4B | mim-catalysis | R-HSA-72647 (Reactome) | ||
| EIF4E | Arrow | R-HSA-72619 (Reactome) | ||
| EIF4E | Arrow | R-HSA-72622 (Reactome) | ||
| EIF4EBP1 | Arrow | R-HSA-72622 (Reactome) | ||
| EIF4E | R-HSA-72631 (Reactome) | |||
| EIF4G1 | Arrow | R-HSA-72619 (Reactome) | ||
| EIF4G1 | R-HSA-72631 (Reactome) | |||
| EIF4H | Arrow | R-HSA-72619 (Reactome) | ||
| EIF4H | R-HSA-72647 (Reactome) | |||
| EIF4H | mim-catalysis | R-HSA-72647 (Reactome) | ||
| EIF5 | Arrow | R-HSA-72619 (Reactome) | ||
| EIF5 | Arrow | R-HSA-72697 (Reactome) | ||
| EIF5 | R-HSA-72619 (Reactome) | |||
| EIF5 | R-HSA-72697 (Reactome) | |||
| GDP | Arrow | R-HSA-72722 (Reactome) | ||
| GTP | Arrow | R-HSA-72669 (Reactome) | ||
| GTP | R-HSA-72663 (Reactome) | |||
| GTP | R-HSA-72722 (Reactome) | |||
| L13a kinase | mim-catalysis | R-HSA-156832 (Reactome) | ||
| Met-tRNAi | R-HSA-72669 (Reactome) | |||
| PABPC1 | R-HSA-156808 (Reactome) | |||
| Pi | Arrow | R-HSA-72619 (Reactome) | ||
| Pi | Arrow | R-HSA-72621 (Reactome) | ||
| Pi | Arrow | R-HSA-72647 (Reactome) | ||
| Pi | Arrow | R-HSA-72671 (Reactome) | ||
| R-HSA-156808 (Reactome) | The precise order of events leading to the circularization of poly (A) mRNA during translation initiation is unknown. Here the association of PABP with the poly (A) mRNA and the association of PABP with eIF4F are represented as occuring simultaneously after formation of the initiation complex. However, it is also possible that these interactions occur during the formation of the translation initiation complex. The binding of eIF4F to the cap and binding of PABP to the poly (A) tail, for example, may occur at the same time. In fact, the eIF4G-PABP interaction helps eIF4F to bind tighter to the cap (Borman et al. 2000.) In addition, eIF4B and eIF4H bind more transiently to the mRNA and may not be part of an initial complex in which PABP has not yet touched eIF4G. | |||
| R-HSA-156823 (Reactome) | Although the mechanism through which L13a prevents translation initiation has not been determined, Mazumder et al. (2003) have described four alternatives. L13a could (1) inhibit the function of eIF4F, (2) block the recruitment of the 43S preinitiation complex, (3) prevent scanning of the 43S complex to the initiation codon, or 4) interfere with joining of the 60S ribosomal subunit. | |||
| R-HSA-156826 (Reactome) | The L13a subunit of the 60s ribosome is phosphorylated about 16 hours after INF gamma induction by an unknown kinase. At this time, L13a is also released from the 60s subunit (Mazumder et al.,2003). It is unclear, however, whether phosphorylation occurs before or after the release of L13a. Here, phosphorylation is shown as occurring after release. | |||
| R-HSA-156832 (Reactome) | The L13a subunit of the 60s ribosome is phosphorylated about 16 hours after INF gamma induction by an unknown kinase. At this time, L13a is also released from the 60s subunit (Mazumder et al.,2003). It is unclear, however, whether phosphorylation occurs before or after the release of L13a. Here, phosphorylation is shown as occurring after release. | |||
| R-HSA-157849 (Reactome) | The translation initiation complex forms when the 43S complex binds the mRNA that is associated with eIF4F, eIF4B and eIF4H. eIF4G in the eIF4F complex can directly contact eIF3 in the 43S complex. eIF1A is necessary for the formation of this complex. | |||
| R-HSA-72619 (Reactome) | Once the Met-tRNAi has recognized the AUG, eIF2-bound GTP is hydrolyzed. The reaction is catalyzed by eIF5 (or eIF5B) and is thought to cause dissociation of all other initiation factors and allow joining of the large 60S ribosomal subunit. Release of the initiation factors from 40S leaves the Met-tRNAi in the ribosomal P-site base-paired to the start codon on the mRNA. | |||
| R-HSA-72621 (Reactome) | The mRNA-bound ribosomal complex moves along the 5'-untranslated region (5'-UTR) of the mRNA from its initial site to the initiation codon to form a 48S complex, in which the initiation codon (AUG) is base paired to the anticodon of the Met-tRNAi. It is not known whether eIF4A (or another ATPase, such as DED1) facilitates scanning by melting mRNA secondary structures or by actively propelling the ribosome. | |||
| R-HSA-72622 (Reactome) | eIF4E gets released from the inactive eIF4E:4EBP complex. | |||
| R-HSA-72631 (Reactome) | eIF4A interacts with eIF4G, and eIF4E interacts with the amino-terminal domain of eIF4G to form the cap-binding complex eIF4F. | |||
| R-HSA-72635 (Reactome) | The factor eIF4E within the eIF4F (cap-binding) complex directly binds the 5'-cap on eukaryotic mRNAs. Note that the mRNA is in complex with cytoplasmic proteins constituting an mRNP complex. | |||
| R-HSA-72647 (Reactome) | The DEAD-box RNA helicase eIF4A, together with the RNA-binding proteins eIF4B or eIF4H, is thought to unwind RNA secondary structures near the 5'-end of the mRNA and in the presence of ATP. | |||
| R-HSA-72663 (Reactome) | Activation of eIF2 through direct binding of GTP. | |||
| R-HSA-72669 (Reactome) | The ternary complex forms upon binding of the initiator methionyl-tRNA to the active eIF2:GTP complex. | |||
| R-HSA-72670 (Reactome) | Inactive eIF2:GDP binds eIF2B to form an eIF2:GDP:eIF2B intermediate. | |||
| R-HSA-72671 (Reactome) | Once the 60S subunit joins the translation initiation complex, eIF5B hydrolyzes its GTP and is released from the now 80S monosome. The fully assembled 80s ribosome is now ready to start elongation of the polypeptide chain. | |||
| R-HSA-72672 (Reactome) | Joining of the 60S subunit to form the 80S ribosome is catalyzed by the presence of GTP-bound eIF5B. | |||
| R-HSA-72673 (Reactome) | 80S monosomes dissociate into 40S and 60S ribosomal subunits. eIF1A promotes this dissociation. | |||
| R-HSA-72676 (Reactome) | eIF3 and eIF1A bind to the 40S ribosomal subunit. | |||
| R-HSA-72691 (Reactome) | The ternary complex (Met-tRNAi:eIF2:GTP) binds to the complex formed by the 40S subunit, eIF3 and eIF1A, to form the 43S complex. eIF1A promotes binding of the ternary complex to the 40S subunit within 43S. The initiator methionyl-tRNA from the ternary complex is positioned at the ribosomal P site. | |||
| R-HSA-72697 (Reactome) | The AUG initiation codon in the mRNA is recognized by base pairing with the anticodon of the Met-tRNAi. This reaction requires eIF1, eIF1A, eIF2 and eIF5. | |||
| R-HSA-72722 (Reactome) | eIF2B is a guanine nucleotide releasing factor that is required to cause GDP release so that a new GTP molecule can bind and activate eIF2, so that it can be reused. | |||
| RNA-binding protein
in RNP (ribonucleoprotein) complexes | Arrow | R-HSA-72647 (Reactome) | ||
| RPL13A | Arrow | R-HSA-156826 (Reactome) | ||
| RPL13A | R-HSA-156832 (Reactome) | |||
| eIF1 | Arrow | R-HSA-72697 (Reactome) | ||
| eIF1 | R-HSA-72619 (Reactome) | |||
| eIF1 | R-HSA-72697 (Reactome) | |||
| eIF1 | mim-catalysis | R-HSA-72621 (Reactome) | ||
| eIF1 | mim-catalysis | R-HSA-72697 (Reactome) | ||
| eIF2:GDP: eIF2B | Arrow | R-HSA-72670 (Reactome) | ||
| eIF2:GDP: eIF2B | R-HSA-72722 (Reactome) | |||
| eIF2:GDP | Arrow | R-HSA-72619 (Reactome) | ||
| eIF2:GDP | R-HSA-72670 (Reactome) | |||
| eIF2:GTP | Arrow | R-HSA-72663 (Reactome) | ||
| eIF2:GTP | Arrow | R-HSA-72722 (Reactome) | ||
| eIF2:GTP | R-HSA-72669 (Reactome) | |||
| eIF2B subunits complex | Arrow | R-HSA-72722 (Reactome) | ||
| eIF2B subunits complex | R-HSA-72670 (Reactome) | |||
| eIF2B subunits complex | mim-catalysis | R-HSA-72722 (Reactome) | ||
| eIF3 subunits complex | Arrow | R-HSA-72619 (Reactome) | ||
| eIF3 subunits complex | R-HSA-72676 (Reactome) | |||
| eIF4A subunits complex | Arrow | R-HSA-72619 (Reactome) | ||
| eIF4A subunits complex | Arrow | R-HSA-72647 (Reactome) | ||
| eIF4A subunits complex | R-HSA-72631 (Reactome) | |||
| eIF4A subunits complex | R-HSA-72647 (Reactome) | |||
| eIF4A subunits complex | mim-catalysis | R-HSA-72647 (Reactome) | ||
| eIF4E:4E-BP | R-HSA-72622 (Reactome) | |||
| eIF4F:mRNP | Arrow | R-HSA-72635 (Reactome) | ||
| eIF4F:mRNP | R-HSA-72647 (Reactome) | |||
| eIF4F | Arrow | R-HSA-72631 (Reactome) | ||
| eIF4F | R-HSA-72635 (Reactome) | |||
| eIF5B:GDP | Arrow | R-HSA-72671 (Reactome) | ||
| eIF5B:GTP | R-HSA-72672 (Reactome) | |||
| mRNA:eIF4F:eIF4B:eIF4H | Arrow | R-HSA-72647 (Reactome) | ||
| mRNA:eIF4F:eIF4B:eIF4H | R-HSA-157849 (Reactome) | |||
| mRNP | R-HSA-72635 (Reactome) | |||
| p-RPL13A | Arrow | R-HSA-156832 (Reactome) | ||
| p-RPL13A | R-HSA-156823 (Reactome) | |||
| phospho-L13a
associated wth the 3' UTR GAIT element of ceruloplasmin mRNA within the translation initiation complex | Arrow | R-HSA-156823 (Reactome) | ||
| ternary complex | Arrow | R-HSA-72669 (Reactome) | ||
| ternary complex | R-HSA-72691 (Reactome) |
