RIBOSOME-MEDIATED TRANSLATIONAL PAUSE AND PROTEIN DOMAIN ORGANIZATION

Because regions on the messenger ribonucleic acid differ in the rate a t which they are translated by the ribosome and because proteins can f old cotranslationally on the ribosome, a question arises as to whether the kinetics of translation influence the folding events in the growi ng nascent polypeptide chain. Translationally slow regions were identi fied on mRNAs for a set of 37 multidomain proteins from Escherichia co li with known three-dimensional structures. The frequencies of individ ual codons in mRNAs of highly expressed genes from E. coli were taken as a measure of codon translation speed. Analysis of codon usage in sl ow regions showed a consistency with the experimentally determined tra nslation rates of codons; abundant codons that are translated with fas ter speeds compared with their synonymous codons were found to be avoi ded; rare codons that are translated at an unexpectedly higher rate we re also found to be avoided in slow regions. The statistical significa nce of the occurrence of such slow regions on mRNA spans corresponding to the oligopeptide domain termini and linking regions on the encoded proteins was assessed. The amino acid type and the solvent accessibil ity of the residues coded by such slow regions were also examined. The results indicated that protein domain boundaries that mark higher-ord er structural organization are largely coded by translationally slow r egions on the RNA and are composed of such amino acids that are sticki er to the ribosome channel through which the synthesized polypeptide c hain emerges into the cytoplasm. The translationally slow nucleotide r egions on mRNA possess the potential to form hairpin secondary structu res and such structures could further slow the movement of ribosome. T he results point to an intriguing correlation between protein synthesi s machinery and in vivo protein folding. Examination of available muta genic data indicated that the effects of some of the reported mutation s were consistent with our hypothesis.