The process of ribosomal recoding is generally regulated by an autonomous mRNA signal downstream of stop-codons. While structural studies have provided mechanistic insights into viral systems, no such studies exist in mammalian systems. Here we define a novel structural mechanism for the VEGF-A readthrough system and show that regulation is multifaceted and complex, requiring a multipartite set of RNA elements located at long distances that interact with each other and with hnRNP A2/B1 to synergistically enhance readthrough levels. The Ax-element downstream of the stop codon adopts a unique multistem (SL-Ax1-3) architecture: SL-Ax1 interacts with hnRNP A2/B1, while SL-Ax2 interacts with an RNA element (SL-Au1) located ~500 nt upstream at the start of the coding sequence. SL-Au1 also independently binds to hnRNP A2/B1, which manipulates an equilibrium between alternate structures— from a sequestered bulge towards one that allows for the long-range interaction with SL-Ax2. Overall, our study not only highlights the significance of structural organization of elements within the coding sequence of mRNA, but also provides a functional relevance of the closed-loop mRNA organization in non-canonical translation and suggests complex mechanisms allow for finer integration of many signals for a required output.