Figure 9. Working models of translation and LARP-PABP factors.

A) Schematic showing factors involved in an example network of protein-protein and RNA-protein interactions that serve to bridge the 5' and 3' end regions of the mRNA according to a closed loop model of translation. A translation initiation (start) codon AUG, and a termination (stop) codon, UAA are to orient polarity. Individual factors are referred to in the text. Multiple copies of PABP can bind to the poly(A) tail via its four RRM domains (depicted in highly schematized form), some of which also serve as separate docking sites for other factors including eIF4G and Paip1^{166, 178}. The MLLE domain of PABP, depicted as red circles, are used to interact with different PAM2-consensus sequence-containing proteins involved in translation initiation (Paip1), termination (eRF3) or recruitment of deadenylase-containing complexes (CAF1-CCR4 and PAN3-PAN2)^{178, 181}. The eIF4E cap-binding positive initiation factor and its association with eIF4G are depicted ^{for more comprehensive reviews see 168, 169, also see 170}. An inset reveals the eukaryotic mRNA two different cap structures; 5’-TOP mRNAs contain a cap-C (m7GpppC), and other mRNAs contain a cap-G/A (m7Gppp-G/A). Under repressive conditions such as nutritional or other stress, 4E-BPs (eIF4E-binding proteins), sequester the cap binding protein eIF4E. B) A potential working model for LARP1 involvement in mRNA metabolism in relation to translation initiation and stabilization. It can bind via the DM15 domain to the 7mGpppC-TOP motif of TOP mRNAs and to PABP and to poly(A) (or other regions) of the mRNA via its La module (see text), although whether it would do so simultaneously as depicted here is unknown. LARP1 may either stimulate or inhibit translation and stabilize poly(A) under some conditions (see text). C) Proposed working model for LARP4/4B involvement in translation and mRNA stability. LARP4/4B interact with RACK1 and with PABP, although whether either of them would do so simultaneously is unknown, three of the combinatorial possibilities are depicted. LARP4B is proposed to bind to mRNA 3' UTR sequences (¹³ see text). LARP4 has been shown to bind PABP via the PAM2 motif, and through a second PABP-interaction motif (PBM). It is unknown to which part of PABP the PBM binds. LARP4 can also bind poly(A) RNA. Through competition with the PAM2 motifs of the deadenylases for the MLLE domain of PABP, LARP4/4B may protect mRNA 3'-ends from deadenylation, leading to poly(A) length modulation¹¹⁴. 4E-BPs: 4E binding proteins, repressors of translation; Paip1: poly(A) binding protein interacting protein-1, a stimulator of translation; eIF4E: eukaryotic initiation factor 4E, a.k.a., cytoplasmic cap binding protein; eIF4G; eukaryotic initiation factor 4G; eIF3: eukaryotic initiation factor 3; eIF4A: eukaryotic initiation factor 4A; RACK1: receptor for activated kinase C, a 40S ribosome subunit; eRF1 and eRF3 are eukaryotic translation termination/release factors. Tob2: transducer of ERBB2; CAF1-CCR4: chromatin assembly factor 1 and CCR4-NOT transcription complex subunit 6, two proteins with poly(A) deadenylase activity; PAN2: PAB-dependent poly(A)-specific ribonuclease subunit PAN2, catalytic subunit of the poly(A)-nuclease (PAN) deadenylation complex; PAN3: PAB-dependent poly(A)-specific ribonuclease subunit PAN3, regulatory subunit of the poly(A)-nuclease (PAN) deadenylation complex.