A research team at IFOM in Milan has perfected a sophisticated technique that allowed them to capture a molecular snapshot of the process coordinated by ubiquitin.

This is a protein with a complex role in cellular communication crucial for the health of the organism.

Malfunctions in the communication mechanism managed by ubiquitin can give rise to tumours, as seen in ovarian cancer.

The study, published in the authoritative scientific journal Nature Structural and Molecular Biology was conducted using an innovative technology developed by IFOM in collaboration with the X-ray Crystallography Unit at the IEO.

Communication is a key aspect of the life of a cell: It constitutes the system through which the cell coordinates all internal and external biological events and responds to possible changes.

Among the languages that cells use to communicate, scientists now consider ubiquitination - the addition of ubiquitin to a protein - to be one of the most complex and fascinating. Until little more than a decade ago, ubiquitination was thought to carry only one message: destruction of proteins labeled with this specific molecular signal.

In recent years, the decisive contribution of research conducted by Simona Polo, a researcher from Milan who heads the Ubiquitination and Signal Transmission program at IFOM and conducts research at the Department of Health Sciences, University of Milan, has revealed a much more complex function of ubiquitin in the communication between internal and external cellular environments: it is a multitasking protein, capable of transmitting multiple signals - activation, degradation, localization, interaction, and more - to a variety of protein factors.

The proper execution of this ubiquitin function is essential for the life of cells and tissues and, ultimately, to the organism: when the message is not transmitted and interpreted faithfully, the cell runs the risk of proliferating uncontrollably, moving toward malignant transformation and giving rise to cancers.

"Over the years we have shown that ubiquitin has multitasking capabilities and plays a fundamental role in the health of the organism - says Simona Polo - but catching ubiquitin in action was an extremely difficult challenge because the process that it performs occurs in an instant, making it impossible to see with traditional techniques."

Thanks to innovative technology, developed in close collaboration with the Crystallography Unit in the Department of Experimental Oncology at IEO, Simona Polo and her team have succeeded in capturing the first molecular snapshots of the rapid ubiquitination process, which until now remained elusive to scientists. This research, which lays the foundation for a more detailed understanding of the molecular mechanisms triggered by ubiquitination, was described yesterday in the authoritative scientific journal Nature Structural and Molecular Biology.

To crack the ubiquitin code the team led by Polo has made use of sophisticated techniques such as X-ray crystallography, developed in collaboration with the IEO team led by Sebastiano Pasqualato. "Intimately exploring the architecture of the molecules by means of X-ray crystallography allowed us to view the function of ubiquitin in three-dimensions and catch the transient process that is triggered in the cell at the molecular level. To develop this molecular photograph we generated protein crystals in laboratories at IFOM and IEO, and analyzed them with X-rays at the European synchrotron in Grenoble, the ESRF."

But why is ubiquitin important in cancer research? "The cellular processes regulated by ubiquitination are numerous and potentially affect all aspects of the life of a cell." explains Simona Polo, "As a result numerous signal transmission routes would be seriously compromised if this mechanism were altered, giving rise to various types of cancer. Our challenge is to identify and study both the main components and the accessory elements of the ubiquitin system, which may allow us to identify new therapeutic targets." 

Emblematic of this is BRCA1, a protein involved in the response to DNA damage that functions by transferring a ubiquitin molecule to its target. Mutations in the BRCA1 gene are clearly associated with breast and ovarian cancer: in tumour cells, BRCA1 is mutated and no longer able to mediate ubiquitination, a process essential for the recognition and repair of DNA damage.

Ovarian cancer is an example, but there are many cases in which the initiation or progression of a tumour results from a malfunction in the ubiquitination process.

"This study - the scientist explains - helps us to better understand the molecular mechanisms underlying these diseases and to identify targets in the ubiquitin communication system for the development of new therapeutic approaches. It is certainly a difficult result to understand, but once again it demonstrates the importance basic research for laying the groundwork leading to the identification of targeted therapeutic approaches."

The research conducted in IFOM by Simona Polo was made possible thanks to the support of AIRC, EMBO and the European Community.

Original title: “Structure of a ubiquitin-loaded HECT ligase reveals the molecular basis for catalytic priming” Nature Structural & Molecular Biology, May 5, 2013

Source: IFOM