Control not at initiation? Bah, humbug!

Abstract

Initiation is often assumed to be rate-limiting for protein synthesis, but the presence of rare codons nonetheless can influence protein levels. In this issue of The EMBO Journal, Chu et al report that when rare codons are positioned near the start of the coding region, 'liberation' of the initiation codon for loading of the next 40S subunit may be rate‐limiting for initiation and therefore overall protein synthesis. The sequential nature of translation results in an interdependence in ribosome association either by de novo initiation or recycling. Thus, a more general view emerges where both elongation and initiation can contribute to protein expression.

Figure 1

In this simple example the net rate constant for initiation is k_obs = k_init k_lib / (k_init + k_lib). On the left is an example of the cases in which k_lib is fast relative to k_init (blue line, k_lib = 10) and in which k_lib is slow relative to k_init (red line, k_lib = 1). These rate constants are pseudo-first order and have units of reciprocal time. On the right is a Gibbs free energy profile of the extreme cases in which k_init is rate limiting (blue line) or k_lib (red line) is rate limiting.