From ribosomal rotation to autism and cancer

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The ribosome transits between two main conformational states, non-rotated and rotated, as it progresses through the translation elongation cycle. How this transition is controlled is not known. Here, we present evidence that the essential ribosomal protein L10 regulates this process in yeast ribosomes through a flexible loop located within 13 Å of the peptidyltransferase center. While deletion of the entire loop is lethal, viable mutants in this region were found to promote opposing effects on the natural equilibrium between the two conformational states of the ribosome. Mutants causing rotational disequilibria show defects in essential ribosomal processes including ligand binding, peptidyltransfer, decoding, reading frame maintenance, and gene expression. Large-scale chemical modification analyses of rRNA of the mutant ribosomes identified networks of near-, medium-, and long-range allosteric interactions involved in coordinating intersubunit rotation. These allosteric pathways map from L10 in the core of the large subunit and propagate outward through both subunits, linking all of the functional centers of the ribosome. Mutants of ribosomal protein L3 promoting opposing structural effects suppress the effects of the L10 mutants by re-establishing the correct rotational equilibrium. This loop is also involved in recruitment of the biogenesis factor Sdo1p as part of a quality control mechanism in which pre-60S subunits undergo a “test drive” before maturation. This suggests that the correct rotational status is important for ensuring late-stage maturation of the large subunit, indicating that the L10 loop is a key regulator of ribosome function throughout the ribosomal life cycle. A model is presented describing how the unidirectionality of translation and ribosomal rotation are powered by this intrinsic mobile loop. Additionally, mutants in this element have been identified in a fraction of T-cell acute lymphoblastic leukemia patients, and these mutants were found to also favor the rotated state. This suggests that a rotational disequilibrium is at the heart of this disease, and a mechanistic model is presented that describes how a ribosomal mutation can lead to cancer, and identifies new treatments. Moreover, analysis of mutations in the essential C-terminal end of L10 linked with autism has provided functional insight into the mechanism of this disorder.