The role of mRNA competition in regulating translation. IV. Kinetic model.

A kinetic model of protein synthesis is presented, primarily designed to analyze the accompanying data (Brendler, T., Godefroy-Colburn, T., Carlill, R. D., and Thach, R. E. (1981) J. Biol. Chem. 256, 11747-11754; Walden, W. E., Godefroy-Colburn, T., and Thach, R. E. (1981) J. Biol. Chem. 256, 11739-11746). Our model treats initiation as a multistep process in which mRNA must bind to a "discriminatory factor" prior to its recognition by the native 40 S subunit. Interaction with the latter is followed by an irreversible rearrangement which yields the functional 40 S initiation complex capable of binding the 60 S ribosome with release of all the factors. Elongation is simply treated as a series of irreversible steps with a single rate constant. The model takes into account the recycling of ribosomal subunits, initiation factors, discriminatory factor, and message initiation site. We can thus mimic the simultaneous translation of several messages, each with its own concentration, size, binding constants, and rate constants. The only limit to the number of messages is the capacity of the computer (3 kilobytes of accessible memory is sufficient for 5 messages). Thus, we are able to evaluate quantitatively the effect of each parameter on the rate of synthesis of individual polypeptides, on polysome size, and on the repartition of message species between the untranslated and the polysomal pools. Several applications are considered: (i) competitive translation of alpha- and beta-globin in vitro (Kabat, D., and Chappel, M. R. (1977) J. Biol. Chem. 252, 2684-2690); (ii) determination of the relative affinities of reoviral messages for the discriminatory factor in vitro (Brendler, T., Godefroy-Colburn, T., Carlill, R. D., and Thach, R. E. (1981) J. Biol. Chem. 256, 11747-11754); (iii) effect of elongation inhibitors on the translation of reoviral and cellular messages in SC-1 fibroblasts (Walden, W. E., Godefroy-Colburn, T., and Thach, R. E. (1981) J. Biol. Chem. 256, 11739-11746); and (iv) effect of the growth state on the initiation efficiency of Vero cell messages (Lee, G. T.-Y., and Engelhardt, D. L. (1979) J. Mol. biol. 129, 221-233). In each case we find that the experimental data are consistent with the notion that mRNAs compete for a discriminatory factor independent of the ribosome. This factor has a high enough affinity for mRNAs to ensure nearly quantitative binding. When present in a limiting amount (with respect to the message pool but not necessarily with respect to the rest of the translation apparatus), the discriminatory factor selects against those messages for which its affinity is lowest, thereby modulating their initiation efficiency. When the factor is present in excess, on the other hand, all the messages are translated at maximum efficiency. This form of translational control could be remarkably efficient as an on-off switch for the synthesis of a few key proteins.