Submitted by Penny Peck on Fri, 27/11/2020 - 17:25
Venki Ramakrishnan (MRC LMB) and his research group, in a collaboration with Michal Minczuk, obtained cryo-EM structures of mitorobosomes purified from human cell line known to have a high propensity for ribosome stalling. This cellular model was generated by Michal’s group as a part of the PhD project of Sarah Pearce. Exhaustive analysis of the cryo-EM datasets allowed them to capture structures of most of the steps in the mitoribosomal elongation cycle as well as uncover a novel rescue pathway involving a release factor C12orf65, renamed mtRF-R, and its binding partner, an RNA binding protein, MTRES1. Their structures show that these rescue factors function on the large mitoribosomal subunit of stalled and split ribosomes, to eject the nascent polypeptide chain and release the peptidyl tRNA.
This work sets the stage for further understanding of the regulation of gene translation in mitochondria. A detailed comparison of ribosomal function in mitochondria versus bacteria would benefit our understanding of why some antibiotics might have unwanted effects on the function of our own cells. Furthermore, mutations in mtRF-R have been associated with neurological disorders, including optic atrophy, peripheral neuropathy, and spastic paraparesis. The discovery of its role in mitoribosomal rescue can help provide a molecular understanding of why mutations in this protein cause disease.
This work is published in Science: Elongational stalling activates mitoribosome-associated quality control. Desai, N., Yang, H., Chandrasekaran, V., Kazi, R., Minczuk M., Ramakrishnan, V. Science, 370(6520): 1105-1110.