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30th January 2017

First 3-D observation of protein complexes working inside cells

Researchers have combined genetic engineering, super-resolution microscopy and biocomputation to witness in 3-D the protein machinery inside living cells. Their method unveils key functional features of protein assemblies that are vital for life, and will make it possible to study cellular protein machinery in health and in disease.


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Left: in vivo image of nanomachines using current microscopy techniques. Right: the new method allows 3-D observation of nanomachines in vivo and provides a 25-fold improvement in resolution. Credit: O. Gallego, IRB Barcelona


Scientists at the Institute for Research in Biomedicine (IRB Barcelona) have published a study in which they observed protein nanomachines (also called protein complexes) – the structures responsible for performing cell functions – for the first time in living cells and in 3-D. This work was done in collaboration with researchers at the University of Geneva in Switzerland and the Centro Andaluz de Biología del Desarrollo in Seville.

Currently, biologists who study the function of protein nanomachines isolate these complexes in test tubes, divorced from the cell, and then apply in vitro techniques that allow them to observe their structure up to the atomic level. Alternatively, they use techniques that allow the analysis of these complexes within the living cell, but that give little structural information. In this latest study, however, the scientists have managed to directly observe the structure of the protein machinery in living cells while it is executing its function.

"In vitro techniques allow us to make observations at the atomic level, but the information provided is limited," explains Oriol Gallego, IRB Barcelona researcher and study coordinator. "We will not know how an engine works if we disassemble it and only look at the individual parts. We need to see the engine assembled in the car and running. In biology, we still do not have the tools to observe the inner workings of a living cell, but the technique that we have developed is a step in the right direction. We can now see, in 3-D, how the protein complexes carry out their functions."

The new technique combines super-resolution microscopy – a discovery that was recognised with the 2014 Nobel Prize in Chemistry – cell engineering, and computational modelling. This enables the observation of protein complexes with a precision of 5 nanometres (nm), a resolution "four times better than that offered by super-resolution and that allows us to perform cell biology studies that were previously unfeasible," explains Gallego (*a nm is a millionth of a mm. Human hairs have a width of 100,000 nm).




Cells were genetically modified by the researchers to build artificial supports inside, onto which they could anchor protein complexes. The supports were designed in such a way as to allow them to regulate the angle from which the immobilised nanomachinery was viewed. The 3-D structure of protein complexes was then determined by using super-resolution techniques to measure distances between the different components, then integrating them in a process similar to that used by GPS.

Gallego used this method to study exocytosis, a mechanism that the cell uses to communicate with the cell exterior. For instance, neurons communicate with each other by releasing neurotransmitters via exocytosis. Their study allowed the scientists to reveal the entire structure of a key nanomachine in exocytosis that until now was an enigma: "We now know how this machinery, which is formed by eight proteins, works and what each protein is important for," said Gallego. "This knowledge will help us to better understand the involvement of exocytosis in cancer and metastasis – processes in which this nanomachinery is altered."

The study is published in the journal Cell.


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