Translation - Regulation of translation initiation

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).

eIF1, eIF2/GTP/tRNA^met, eIF3 and eIF5 form multifactor complex (MFC) [1], [2].

eIF2 functions by forming complex eIF2/GTP/tRNA^met at 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 subunits [3].

eIF2 is activated by guanine nucleotide exchange factor eIF2B, which composed of 5 subunits termed eIF2B1-5 in order of increasing size [4]. 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 [5].

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 [2].

40S ribosome subunit binds to eIF1A and eIF3, which prevents association of 40S with 60S subunit [6].

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 [7].

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 [8].

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 [9].

Poly(A) binding proteins, cytoplasmic (PABPCs) stimulates translation by binding to eIF4Gs and poly(A) tail mRNA activation [10].

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 [2]. 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 [6].

60S subunits are activated by release of eIF6. It may operate through interaction with guanine nucleotide-binding protein beta subunit-like protein 12.3 (RACK1) [11].

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 [6].

References:

1. Valásek L, Nielsen KH, Hinnebusch AG
   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
2. Singh CR, He H, Ii M, Yamamoto Y, Asano K
   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
3. Kimball SR
   Eukaryotic initiation factor eIF2. The international journal of biochemistry & cell biology 1999 Jan;31(1):25-9
4. Wang X, Paulin FE, Campbell LE, Gomez E, O'Brien K, Morrice N, Proud CG
   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
5. Krishnamoorthy T, Pavitt GD, Zhang F, Dever TE, Hinnebusch AG
   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
6. 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
7. 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. Genes & development 2000 Oct 1;14(19):2534-46
8. Pyronnet S, Imataka H, Gingras AC, Fukunaga R, Hunter T, Sonenberg N
   Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E. The EMBO journal 1999 Jan 4;18(1):270-9
9. Raught B, Gingras AC, Sonenberg N
   The target of rapamycin (TOR) proteins. Proceedings of the National Academy of Sciences of the United States of America 2001 Jun 19;98(13):7037-44
10. Kahvejian A, Svitkin YV, Sukarieh R, M'Boutchou MN, Sonenberg N
    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
11. Ceci M, Gaviraghi C, Gorrini C, Sala LA, Offenhäuser N, Marchisio PC, Biffo S
    Release of eIF6 (p27BBP) from the 60S subunit allows 80S ribosome assembly. Nature 2003 Dec 4;426(6966):579-84