Regulation of translation initiation
The synthesis of a new protein is a highly regulated process that allows rapid
cellular responses to diverse stimuli in the absence of transcription. Translation rates
can be controlled at each of the three steps of translation: initiation, elongation and
termination. However, regulation occurs predominantly at initiation. Translation
initiation consists of several steps and is catalyzed by proteins known as eukaryotic
initiation factors (eIFs).
eIF3 and eIF5 form multifactor
complex (MFC) , .
eIF2 functions by forming complex
the early steps of protein synthesis. The eIF2 is composed
of 3 nonidentical subunits, eIF2S1-3, and catalyzes the
first regulated step of protein synthesis initiation, promoting the binding of the
initiator tRNA to 40S ribosomal
eIF2 is activated by guanine nucleotide exchange factor
eIF2B, which composed of 5 subunits termed
eIF2B1-5 in order of increasing size . In
addition, phosphorylation of eIF2S1 leads by protein kinases
to more extensive interactions between eIF2S1 and the
regulatory subcomplex, preventing productive interactions between
eIF2B5 and the eIF2S2 and
eIF2S3, inhibiting nucleotide exchange .
MFC complex interacts with the 40S
ribosome subunit and as a result 43S
pre-initiation complex forms. The accumulating evidence supports the model that the
constituents of the MFC bind to the 40
S ribosome subunit as a preformed unit to form the 43
S complex .
40S ribosome subunit binds to
eIF1A and eIF3, which prevents association of
40S with 60S subunit .
43S preinitiation complex requires only the addition of
the mRNA/eIF4F/PABPC complexes to produce a
48S complex capable of locating the AUG start codon and
hydrolyzing the GTP bound to eIF2 .
The eIF4F complex consists of
eIF4G, eIF4E and
eIF4A. eIF4G serves as a
scaffold protein for the assembly of eIF4E and
eIF4A. There are two functional homologs of mammalian
eIF4G, termed eIF4G1 and
eIF4G3, which share 46% identity and have similar
biochemical activities .
Ribosomal protein 6S kinases, 70-kD (p70S6K1 and
p70S6K2) (which regulate of activity
eIF4F complex) has part in phosphorylation of
40S ribosomal protein S6
(RPS6). RPS6 phosphorylation is
thought to promote the selective translation of a subset of transcripts, primarily
ribosomal protein and elongation factor mRNAs with a
5'-terminal oligopyrimidine tract .
Poly(A) binding proteins, cytoplasmic (PABPCs) stimulates
translation by binding to eIF4Gs and poly(A) tail
mRNA activation .
Further, the 48 S complex searches for the first AUG
codon in the mRNA with the help of low molecular weight
factors, eIF1 and eIF1A, and
the helicase eIF4A . Following recognition
of the AUG codon by tRNA, the GTPase-activating protein
eIF5 stimulates hydrolysis of GTP binding with
eIF2, with release of eIF2-GDP
and other factors from the ribosome .
60S subunits are activated by release of
eIF6. It may operate through interaction with guanine
nucleotide-binding protein beta subunit-like protein 12.3
Further, 40S complex joins with the
60S subunit to form the 80S initiation complex in a reaction
stimulated by eIF5B and eIF1A,
which form bridge between subunits .
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Direct eIF2-eIF3 contact in the multifactor complex is important for translation initiation in vivo.
The EMBO journal 2002 Nov 1;21(21):5886-98
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Efficient incorporation of eukaryotic initiation factor 1 into the multifactor complex is critical for formation of functional ribosomal preinitiation complexes in vivo.
The Journal of biological chemistry 2004 Jul 23;279(30):31910-20
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Eukaryotic initiation factor eIF2.
The international journal of biochemistry & cell biology 1999 Jan;31(1):25-9
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Eukaryotic initiation factor 2B: identification of multiple phosphorylation sites in the epsilon-subunit and their functions in vivo.
The EMBO journal 2001 Aug 15;20(16):4349-59
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Tight binding of the phosphorylated alpha subunit of initiation factor 2 (eIF2alpha) to the regulatory subunits of guanine nucleotide exchange factor eIF2B is required for inhibition of translation initiation.
Molecular and cellular biology 2001 Aug;21(15):5018-30
- Olsen DS, Savner EM, Mathew A, Zhang F, Krishnamoorthy T, Phan L, Hinnebusch AG
Domains of eIF1A that mediate binding to eIF2, eIF3 and eIF5B and promote ternary complex recruitment in vivo.
The EMBO journal 2003 Jan 15;22(2):193-204
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A multifactor complex of eukaryotic initiation factors, eIF1, eIF2, eIF3, eIF5, and initiator tRNA(Met) is an important translation initiation intermediate in vivo.
Genes & development 2000 Oct 1;14(19):2534-46
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Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E.
The EMBO journal 1999 Jan 4;18(1):270-9
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The target of rapamycin (TOR) proteins.
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Mammalian poly(A)-binding protein is a eukaryotic translation initiation factor, which acts via multiple mechanisms.
Genes & development 2005 Jan 1;19(1):104-13
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Release of eIF6 (p27BBP) from the 60S subunit allows 80S ribosome assembly.
Nature 2003 Dec 4;426(6966):579-84