Kinetic Proofreading Scanning Models for Eukaryotic Translational Initiation: the Cap and Poly(A) Tail Dependency of Translation

Abstract

Two simplified kinetic proofreading scanning (KPS) models were proposed to describe the 5′ cap and 3′ poly(A) tail dependency of eukaryotic translation initiation. In Model I, the initiation factor complex starts scanning and unwinding the secondary structure of the 5′ untranslated region (UTR) from the 5′ terminus of mRNA. In Model II, the initiation factor complex starts scanning from any binding site in the 5′ UTR. In both models, following ATP hydrolysis, the initiation factor complex either dissociates from mRNA or continues to scan and unwind RNA secondary structure in the 5′ UTR. This step repeats n times until the AUG codon is reached. These two models show very different cap and/or poly(A) tail dependency of translation initiation. The models predict that both cap and poly(A) tail dependencies of translation, and translatability of mRNAs are coupled with the structure of 5′ UTR: the translation of mRNA with structured 5′ UTR is strongly cap- and poly(A) tail-dependent; while translation of mRNA with unstructured 5′ UTR is less cap- and poly(A) tail-dependent. We use these two models to explain: (1) the cap and poly(A) tail dependence of translation; (2) the effect of exogenous poly(A) on translation; (3) repression of host mRNA and translation of late adenovirus mRNA in the late phase of adenovirus infection; (4) repression of host mRNA and translation of Vaccinia virus mRNA in virus-infected cell; (5) heat shock repression of translation of normal mRNA and stimulation of translation of hsp mRNA; and (6) the synergistic effect of cap and poly(A) tail on stimulating translation. The kinetic proofreading scanning models provide a coherent interpretation of those phenomena.