Interaction of polyadenylate-binding protein with the eIF4G homologue PAIP enhances translation

Abstract

In the initiation of translation in eukaryotes, binding of the small ribosomal subunit to the messenger RNA results from recognition of the 5' cap structure (m7GpppX) of the mRNA by the cap-binding complex eIF4F. eIF4F is itself a three-subunit complex comprising the cap-binding protein eIF4E, eIF4A, an ATP-dependent RNA helicase, and eIF4G, which interacts with both eIF4A and eIF4E and enhances cap binding by eIF4E. The mRNA 3' polyadenylate tail and the associated poly(A)-binding protein (PABP) also regulate translational initiation, probably by interacting with the 5' end of the mRNA. In yeast and plants, PABP interacts with eIF4G but no such interaction has been reported in mammalian cells. Here, we describe a new human PABP-interacting protein, PAIP-I, whose sequence is similar to the central portion of eIF4G and which interacts with eIF4A. Overexpression of PAIP-1 in COS-7 cells stimulates translation, perhaps by providing a physical link between the mRNA termini.

Starting the protein synthesis machine: eukaryotic translation initiation

“…(85) It forms complexes of 1:1 stochiometry with PABP, (86) interacts with eIF4A, and was reported to co-activate cap-dependent translationdespite having no eIF4E binding motif. (85) By contrast, Paip2 is a small acidic protein that acts as a translational repressor, with a preferential effect on the translation of polyadenylated mRNAs. (87) Two molecules of Paip2 can simultaneously bind to PABP.…”

DAP5 and IRES-mediated translation during programmed cell death

“…The sequence of the full-length protein shared strong homology to eIF4G (58) and placed this novel gene within this family of scaffold proteins, which has since expanded to also include the PAIPs. 65,66 In addition, detailed sequence alignments showed that the region corresponding to the rescued miniprotein was less conserved within the family members ( Figure 1). Therefore, it was assumed that this miniprotein acted in a dominant-negative manner selectively counteracting the function of the endogenous DAP5 (and not the other family members), thus conferring some resistance to IFN-g during the selection procedure.…”

“…Its mRNA possesses a relatively long 5 0 UTR and a single ORF starting at a GUG initiation codon, which resides within the consensus sequence for non-AUG initiators. [60][61][62][63] The homology to eIF4G 65,66 was restricted to the central segment of eIF4GI/II, which corresponds to the region that binds to eIF4A and eIF3, necessary elements of the translation initiation complex. Interestingly, the N-terminal part of eIF4GI/GII, which mediates the interaction with the mRNA cap structure by direct binding to eIF4E, is completely missing from DAP5 protein (Figure 1).…”

“…Consistent with the structural predictions, it was shown by a few strategies that DAP5/p97/NAT1 indeed binds eIF3 and eIF4A, but fails to bind eIF4E, which is essential for mediating cap-dependent translation. 60,61,63,[65][66][67][68] In this respect, DAP5 resembles the cleaved version of eIF4GI/GII that arises upon picornavirus infection. This structural resemblance raised the possibility that DAP5, like the virally cleaved eIF4GI/II that lost the capbinding features, may maintain the capability to mediate IRES-driven translation under stress conditions.…”

“…The truncated DAP5/p86 is a functional translation factor, which supports its own translation through the IRES element within its 5 0 UTR and independently of the 5 0 cap structure. Furthermore, it was demonstrated that stimulation of DAP5 IRES requires active DAP5 protein, since applying the DAP5 dominant-negative fragment (the 20 Marissen et al, 21 Craig et al 65 and Henis-Korenblit et al 71 Ct tail -C-terminal tail of DAP5/p97 miniprotein isolated in the genetic screen) diminished IRESmediated translation in the in-vitro translation system. 68 Thus, it was confirmed that this self-regulatory event generates a positive feedback loop on DAP5 translation in the dying cell, and allows preferential and continuous production of DAP5 protein under the stress-associated translational block.…”