The Ribosome Uses Cooperative Conformational Changes to Maximize the Efficiency of Protein Synthesis

Abstract

Execution of individual steps in the multi-step functional cycles of large, multi-component molecular machines such as the ribosome almost universally requires remodeling of multiple, spatially distant structural components of the machine. In order to function efficiently, therefore, molecular machines likely must allosterically coordinate numerous, seemingly independent conformational rearrangements. Due to the significant technical challenges associated with characterizing their structural dynamics, however, the questions of whether and how large molecular machines coordinate such dynamics so as to maximize the efficiency with which they perform their biological functions remain exceptionally challenging to answer. Using a combination of structural and phylogenetic analyses, molecular genetics, single-molecule fluorescence resonance energy transfer, and in vitro biochemical assays, here we demonstrate that the ribosome uses cooperative conformational changes to maximize the efficiency with which it translocates and ejects its transfer RNA adaptors during protein synthesis. Interpretation of our data within the context provided by atomic-resolution ribosome structures and phylogenetic analyses of ribosomal RNA and ribosomal protein sequences leads us to propose a structure-based model for the observed cooperativity. Our results demonstrate that large, multi-component, molecular machines such as the ribosome can use networks of cooperative conformational changes to facilitate mechanical processes that would otherwise limit their catalytic rates.