With cryo-electron microscopy, it is possible to examine proteins more than a 1,000 times smaller than the width of a human hair. Now research using the technology may help develop treatment for some of the deadliest forms of cancer.
Professor Guillermo Montoya (on the picture) and his colleagues have used cryo-electron microscopy (cryo-EM) to investigate the protein complex. This technology permits the observation of biomolecules at atomic resolution using a beam of electrons. Photo: Christian Als.
Every year there are almost 4,000 new cases of lung cancer in Denmark, and the disease is responsible for almost as many deaths. Thus, lung cancer is the form of cancer from which most people die in Denmark.
However, new research from the University of Copenhagen can support the development of new treatments for lung cancer and other deadly forms of cancer.
“Our new research shows that it is actually possible to completely destroy this association – i.e. the three proteins.”
“We have unveiled key information that can help destroy the association between a complex of three proteins (RAF-1, HSP90 and CDC37) that causes cancer cells to divide and spread,” says Professor Guillermo Montoya from the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen.
The RAF-1 protein requires the assistance of two other proteins, HSP90 and CDC37, to promote growth of cancer cells, so when the researchers interfere with this association, the uncontrolled and potentially deadly cell division stops.
“The work may open new therapeutic avenues to treating cancers that are otherwise fatal. We can already sense the interest in our work, as there could be therapeutic opportunities in this,” says Guillermo Montoya.
‘The Achilles heel'
Previous research in mice conducted by a group led by the Spanish molecular biochemist Mariano Barbacid at the Spanish National Cancer Research Center (CNIO) has shown that preventing the three proteins from cooperating compromises uncontrolled cell growth.
“In this work, we have cooperated with the Barbacid Group, providing the molecular details of this association. In addition, we have identified a possible ‘Achilles heel’ of the three-protein complex, as modifications in that area lead to the complex dissociation,” says Guillermo Montoya and continues:
“Our new research shows that it is actually possible to completely destroy this association – i.e. the three proteins.”
The three proteins are illustrated here, each in their own color. However, one has two shades of blue. On the right is a depiction of how compact the proteins are. On the left, the proteins are seen from the front and back. Illustration: Guillermo Montoya.
Guillermo Montoya and his colleagues have used cryo-electron microscopy (cryo-EM) to investigate the protein complex. This technology permits the observation of biomolecules at atomic resolution using a beam of electrons.
With cryo-electron microscopy, it is possible to examine proteins that are more than a 1,000 times smaller than the width of a human hair. This is partly due to the development of new direct electron detectors.
“This research would be impossible without the new developments in cryo-EM that allow us to visualise the conformations of flexible protein complexes at high resolution,” says Guillermo Montoya.
A wealth of information
Guillermo Montoya emphasises that while the results in mice that led to this study were encouraging, there is a big difference between mice and humans.
“So we have a lot of work to do in determining whether the information provided by our study can translate into an effective treatment for clinical practice. But if it does work equally well on humans, then it will be a clear advantage in relation to treating cancers where the stabilisation of RAF-1 is a driving force in the development of cancer cells," he says.
Furthermore, Guillermo Montoya points out that the new study provides a basic understanding of how the three proteins work together.
"The important thing is that we have gained detailed knowledge of the protein complex. It offers a wealth of information that other researchers and pharmaceutical companies can work on.”
