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Breakthrough in structural biology reveals ribosome secrets

7 May, 2014

Screen Shot 2014-05-06 at 18.13.26Visualising the intricate machinery in cells is not just about the wonder of seeing the invisible. It also reveals vital information about how our cells work. Michael Regnier reports on a new method of visualising biological structures.

The ribosome is one of our most important cellular machines. It is a protein factory, basically, and there are millions of these factories in each cell. Their job is to follow the genetic instructions and make new proteins, which can then go and do the cell’s work, whether that’s sending signals in the brain or making the heart beat on time.

Dr Venkatraman Ramakrishnan, a Wellcome Trust Senior Investigator, is something of a ribosome paparazzo. He shared the 2009 Nobel Prize in Chemistry for studies of the structure and function of the ribosome – using X-rays instead of visible light to make high-resolution close-up pictures of the various parts that constitute ribosomes and enable them to churn out the billions of proteins our cells need to run properly.

For his latest scoop, published in Science at the end of March 2014, Venki and his team turned the spotlight on the specialised ribosomes that operate in mitochondria. Often described as the batteries of the cell, mitochondria produce the energy that drives cells.

Screen Shot 2014-05-06 at 18.12.58Studying mitochondrial ribosomes is challenging because they make up only a fraction of a per cent of all the ribosomes in a cell. Alexey Amunts, who worked on this research, says the advanced methods that the group has developed to purify mitochondrial ribosomes to make this analysis possible are as important as the biological information that they have uncovered: “It is a breakthrough in structural biology, allowing direct, atomic-level, visualisation of complex biological molecules. The work not only represents the highest resolution limit ever reported by cryo-electron microscopy, better than most ribosomal structures determined by X-ray crystallography, but is also the first time that the atomic structure of a large asymmetric complex has been obtained without crystallization.”

The team found significant differences between mitochondrial ribosomes and ribosomes in the rest of the cell. These differences stem from the fact that mitochondria have their own genes, some of which are used to tweak the basic ribosome design.

For example, mitochondrial ribosomes are permanently tethered to the mitochondrial membrane. Most mitochondrial proteins operate in the membrane, so keeping the ribosome there makes it easier for new proteins to be delivered directly to the right place. Many proteins in the rest of the cell don’t need to be made at a membrane surface, so the ribosomes here tend to float around freely unless they are specifically required to make a membrane protein.

By analysing the mitochondrial ribosome’s structure, the team could tell which part is tied to the membrane, and they could also see that the mitochondrial ribosome pushes its proteins out in a different way to other types of ribosome.

Understanding such subtle differences could be extremely useful. For instance, some antibiotics (in particular a group called aminoglycosides) work by interfering with the ribosomes in bacterial cells – but these drugs cause side-effects because they also affect the ribosomes in our cells and mitochondria. Making such antibiotics more tailored to the fine structure of bacterial ribosomes could reduce toxicity and make them more effective.

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Connecting structure and function works best when you can distinguish features at an atomic level. By identifying an unprecedented level of structural detail, Venki’s group, based at the Medical Research Council Laboratory of Molecular Biology, was able to create new models, and discover new proteins that were previously not known to be associated with mitochondrial ribosomes. Their advanced methods may now be used to resolve the structure of many other low abundance or transient cellular complexes.

The next step for this work is to start visualising ribosomes in their normal cellular environment, giving an ever more intimate representation of the ‘secret lives’ of these molecular celebrities.

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