Leiden researchers visualise the 'guardian of our genome’
The guardian of our genome, the protein MutS, scans the DNA for spelling errors and makes sure they are corrected. An essential process for our health. Researchers at Leiden University Medical Centre (LUMC) have discovered precisely how this protein works by making MutS visible with cryo-electron microscopy. The results have been published in Nature Structure and Molecular Biology.
'MutS has an essential role in our cells,' says researcher Meindert Lamers. 'If this protein is missing, 100 to 1,000 times more mutations occur in our DNA which inevitably leads to cancer. This is the case, for example, in people with Lynch syndrome.'
In other words, it is an important protein. But it was still unknown exactly how this protein works. In an earlier publication, Lamers and colleagues described the structure of MutS. 'Using cryo-electron microscopy, we found out that MutS can have multiple forms,' Lamers explains. 'As a result, it is able to perform many different functions.' After all, it not only scours the DNA for errors, but also hits the alarm when it finds one and calls in the help of assistants. 'Together with these assistants, MutS ensures that the DNA at the crime scene is cut, unravelled and then repaired.'
In follow-up research, the researchers found out how the engine behind MutS works. 'MutS consists of two identical 'hands'. We saw that these hands are constantly opening and closing. But if MutS binds to the DNA, then the DNA stops the two hands from closing. MutS is therefore under a lot of tension when it looks for errors in the DNA.' Since a DNA error makes our genome unstable at that spot, the DNA bends which makes the hands of MutS able to close. As a result, MutS takes on a different form and can call in assistance.
In short, MutS performs molecular acrobatics, allowing it to perform its multiple and crucial functions in our cells. In the video below, the researchers show what MutS looks like and how it changes shape during the whole process.
The guardian of our genome, the protein MutS
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But why is it actually important to map out proteins in detail? 'The structure of a protein determines its function,' Lamers explains. 'You also have to look under the bonnet of a car to find out exactly how it works.' This is no different for the proteins in our body. Cryo-electron microscopy is also used for more practical applications. For example, Lamers' group does a lot of research into antibiotics against tuberculosis. 'By mapping the structure of a new antibiotic and the protein it binds to, we find out exactly how the drug works and are able to optimise it.'
The MutS protein was visualised at the Netherlands Centre for Electron Nanoscopy (NeCEN) using the world's most advanced cryo-electron microscope. This innovative centre is located at the Leiden Bioscience Park and is a collaboration between the Faculty of Science of Leiden University and the LUMC. Researchers, but also companies, from all over the country come to Leiden to study various structures down to the smallest level and in high resolution. For example, these advanced microscopes in Leiden helped to develop Janssen's corona vaccine by mapping the spike protein in detail.
Nature Structure and Molecular Biology wrote a special article in News & Views about the two pulications by Lamers and colleagues on MutS.