The “closed-loop model” of eukaryotic translation initiation states that mRNA is circularized by a chain of interactions between the cap, eIF4E, eIF4G, and the poly(A)-binding protein (PABP)-poly(A) that brings the 5′- and 3′-ends of the mRNA together. The closed-loop model proposes that initiation factors eIF4E, eIF4G, and PABP are required to induce 5′- to 3′-proximity. In this model, associated 5′-cap- and 3′-poly(A) binding proteins mediate the mRNA's circularization. Without these interactions, the intervening RNA loops out, and the ends would be distant.
Cells govern gene expression via translational control to respond to growth and proliferation stimuli and control feedback mechanisms in the cell.
Figure 1: The "closed-loop" model proposes that the induction of 5'- to 3'-proximity requires the initiation factors eIF4E, eIF4G, and PABP (Adapted from Vicens et al.).
Experimental evidence supports the "closed-loop" model. Most eukaryotic mRNAs are capped and contain a poly(A) tail. The model is defined by the cap's interactions, with eIF4E, eIF4G, PABP, and the poly(A) tail. The disruption of these interactions leads to functional effects. PABP binding to poly(A) increases PABP's affinity to eIF4G and the affinity of eIF4E for the cap as well.
In 2015, Archer et al. probed the closed-loop model of mRNA translation in living yeast cells using a combination of tagged translation initiation factors eIF4E, eIF4G, and PAB1. The study results indicated that the closed-loop configuration is detectable for both eIF4F-bound and PAB1-bound heat shock protein SSC1 mRNA in vivo. As a suprise, the closed-loop proportion was much higher for eIF4F-bound than for PAB1-bound SSC1 mRNA. The study showed experimentally that cap-to-tail closed-loop mRNA interactions are formed in living yeast cells. However, the extent of observed closed-loop formation differed between mRNAs.
Recently, Alekhina et al. used continuous in-situ monitoring of the luciferase synthesis in a mammalian in vitro system to determine the translation initiation rate. The study showed that the quality of translation initiation at capped and polyadenylated reporter mRNAs increases after the first ribosomes' time required to complete mRNA translation. The presence of a poly(A)-tail is needed to accelerate the translation initiation rate.
The addition of poly(A) RNA fragments or m7GpppG cap analogs to the translation reaction negates the acceleration. The mRNA's optimal functional interaction requires a 5′-untranslated region (5’-UTR) and a 3′-UTR of moderate length. A longer poly(A) tail appears to slow down the translation initiation rates. According to Alekhina et al., the functional looping enables the recruitment of recycled ribosomes to the start codon of the same mRNA molecule in an eIF4A-independent fashion. This closed-loop assisted re-initiation mode provides efficient translation of functionally circularized mRNAs.
Reference
Olga M. Alekhina, Ilya M. Terenin, Sergey E. Dmitriev, and Konstantin S. Vassilenko; Functional Cyclization of Eukaryotic mRNAs. Int. J. Mol. Sci. 2020, 21(5), 1677. [Article]
Archer SK, Shirokikh NE, Hallwirth CV, Beilharz TH, Preiss T. Probing the closed-loop model of mRNA translation in living cells. RNA Biol. 2015;12(3):248-54. [PMC]
A. KAHVEJIAN, G. ROY, and N. SONENBERG ; The mRNA Closed-loop Model: The Function of PABP and PABP-interacting Proteins in mRNA Translation. Cold Spring Harb Symp Quant Biol 2001. 66: 293-300. [Article]
MARCELO LÓPEZ-LASTRA, ANDREA RIVAS, and MARÍA INÉS BARRÍA; Protein synthesis in eukaryotes: The growing biological relevance of cap-independent translation initiation. Biol Res 38: 121-146, 2005. [PMC]
Wolfgang Tomek & Karin Wollenhaupt; The “closed loop model” in controlling mRNA translation during development. Animal Reproduction Science. Volume 134, Issues 1–2, September 2012, Pages 2-8. [sciencedirect]
Vicens Q, Kieft JS, Rissland OS. Revisiting the Closed-Loop Model and the Nature of mRNA 5'-3' Communication. Mol Cell. 2018 Dec 6;72(5):805-812. [PMC]
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