10 Physical and Functional Interactions between the mRNA Cap Structure and the Poly(A) Tail

Abstract

The 5′-end of all nuclear-encoded messenger RNAs in eukaryotes contains a cap structure (m⁷GpppX). With few exceptions, the 3′-end also contains a poly(A) tail. These structures are added by specific enzymes during or just after mRNA transcription. Not surprisingly, they play important roles in many aspects of mRNA metabolism, including mRNA splicing, transport, stability, localization, and translation. In this chapter, I focus primarily on the role of the poly(A) tail in translation initiation and how it interacts with the 5′-cap structure. The reader is referred to other chapters in this volume for more detailed information on some of these other areas.

THE CAP STRUCTURE AND THE eIF4F COMPLEX
The involvement of the cap structure in mRNA translation was suggested soon after its discovery in the early 1970s (Shatkin 1976). Using an in vitro translation system, it was found that the cap structure stimulated expression of mRNA (Both et al. 1975; Muthukrishnan et al. 1975). Soon after this discovery, the 24-kD protein eIF4E was shown to be associated with the cap structure (Sonenberg et al. 1978). eIF4E could be easily purified from cell extracts by affinity chromatography with m⁷GDP-agarose (Sonenberg et al. 1979). Two other major proteins were found to copurify with eIF4E: The 220-kD protein was named eIF4G, and the 46-kD protein was the already-characterized initiation factor eIF4A. In subsequent years it was shown in both mammalian and yeast systems that eIF4G provided the scaffold to which eIF4E and eIF4A became associated. The complex of eIF4E with eIF4G and eIF4A...