Cancer Related Proteins Mapped
Never known before details of two key complexes of cancer-related proteins revealed by scientists through a complete detailed map of the structures formed when they come together.
It was shown in the study that the arrangement of the individual protein components change in a series of steps when the two protein complexes come together in the cell.
The new insights into this system will help to direct other scientists in their efforts in cancer drug discovery, including in a cutting edge, an emerging field in which finding ways to promote protein degradation using new therapies are aimed by researchers.
At the Institute of Cancer Research, London, and King’s College London, a team of researchers in this study used state-of-the-art equipment to map the structure of the assembly formed between two protein complexes—called the COP9 signalosome () and Cullin-RING E3 Ligase 2 (CRL2).
To deactivate CLR2, CSN binds to it in the cells which in turn leads to the activation of HIF-1 alpha, a third complex that allows more effective growth of tumors. A detailed ‘step-wise’ system was pieced together by the researchers that explained the detailed mechanism of this system, which can drive cancer ultimately.
For
small-molecule drugs, the complex has been proposed as a target, which, to alter its function can ‘lock’ into the protein, and as a target for a new type of drug called PROTACs which recruits E3 ligases like CRL2 to degrade tumor-driving proteins.Clarifying the role of an activating subunit of the CL2 complex, called NEDD8, was one of the key findings of this study. This uncovered the existence of CL2 forms which even without it, seemed to have a biological role.
To make their discoveries, scientists importantly brought together two different types of mass spectrometry and cryo-electron microscopy (cryo-EM).
A range of funders including the Medical Research Council, the Wellcome Trust, the BBSRC, and Cancer Research UK supported this study.
In discovering new targeted cancer drugs, mapping proteins of interest to the cancer research community and in opening up new treatment avenues, the ICR’s Division of Structural Biology scientists played an important role in this work.
The team leader in structural electron microscopy at the ICR, Dr. Edward Morris, the study’s co-leader said ” A range of structural biology techniques were used in our study to generate detailed maps of both the COP9 signalosome and the Cullin-RING E3 Ligase 2, both of which have a range of activities in cells and in some cancers, they have a role when combined.
“With our findings, we hope to influence the wider community of cancer researchers who are looking to discover innovative cancer drugs, like the protein degradation therapies that could target E3 ligases.”
This study is published in the journal Nature Communications.
Editor’s Note: Cancer Related Proteins Mapped, New Understandings from Cancer Related Proteins Mapped
