Unravelling the assembly of the mitoribosome
Researchers from SciLifeLab have revealed the assembly process of the mitochondrial ribosomal small subunit by using cryo-EM. The study describes eight distinct sequential intermediate assembly states and an integrated assembly factor network that might also open new doors in the search for new and more effective antibiotics.
90 percent of our bodies’ energy is produced in the mitochondria by bioenergetic proteins. These essential proteins are synthesizes and maintenance by the mitoribosome complex, consisting of over 80 different components.
The structure and function of the mitoribosomes have been known for almost eight years but the complex manner in how this translational machinery is put together is still not fully understood. Obtaining these pieces of the puzzle is crucial since defects in the mitoribosomal assembly are involved in a large number of metabolic disorders, particularly linked to age-related diseases that are associated with decline in mitochondrial function and biogenesis.
In a recent study, led by SciLifeLab Fellow Alexey Amunts (Stockholm University), researchers have used cryo-EM to analyze a series of intermediate states in the assembly process of the mitoribosome to obtain unique insight into this dynamic process. They identified eight distinct intermediate states in the multi-step assembly pathway, and a sequence of assembly factors interacting with each other as an integrated network.
The atomic level spatial resolution of cryo-EM enabled the researchers to discover a mitochondria-specific protein, mS37, which blocks premature binding of genetic material, as well as essential structural modifications, which occur on the mitoribosomal core at each of the assembly steps.
The results, published in Nature, show that the protein mtIF3 (previously known as “initiation” factor) binds during the assembly, and that mS37 then disrupts its contact. This event marks the completion of the mitoribosome assembly and the initiation of protein synthesis.
The study demonstrates that it is now possible to characterize dynamic processes occurring inside cells, with minimized disruption to the specimen’s native state. Combined with the high spatial resolution of cryo-EM, this have opened the door to new research avenues, such as the visualization of antibiotics bound to mitoribosomes to determine modifications that induce off-target binding and ultimately lead to side effects. This approach could be exploited when designing new and more efficient antibiotics.
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