Some proteins (called chaperones and cochaperones) function to build these protein complexes within cells, and inhibiting this assembly process is being studied as an anticancer strategy. Kinases and enzymes such as mTOR, ATR or telomerase can be compared to buildings under construction, while chaperones such as HSP90 and cochaperones such as R2TP are the machines of construction.
Current evidence suggests that targeting ruvbl1-ruvbl2 has the potential to treat cancer. RUVBL1-RUVBL2 is the power engine that accompanies R2TP. That has led researchers from the DNA damage response unit at the Spanish national cancer research center (CNIO) to use powerful cryo-electron microscopy tools to determine the mechanisms that regulate RUVBL1 and RUVBL2, according to the study published in the journal Science Advances.
As mentioned earlier, the macromolecular complex research group in the DNA damage response determined the high-resolution structure of R2TP using cryogenic electron microscopy. In this study, CNIO researchers looked at how cells design R2TP to make the chaperone protein HSP90 come into contact with the protein it ACTS on. The R2TP complex has an energy engine, a ring of atpases RUVBL1 and RUVBL2 that USES the energy released by ATP hydrolysis to produce ADP. In this energy-generating mechanism, atpase captures ATP in cells and continuously releases ADP as waste and energy.
The scientists found that in the RUVBL1 and RUVBL2 rings, the atp-binding site pathway is completely blocked, and ATP or ADP remains in the ring, which hinders energy exchange and motor work. The question is, how do you use the energy needed to assemble a protein complex?
By looking at the R2TP system under a cryogenic electron microscope, the researchers found the answer. This process USES energy provided by ATP. The key to regulating the opening of this door is the interaction between the R2TP components required for the ATPase RUVBL2 and mTOR assembly.
Studying the structure and dynamics of proteins, that is, understanding the interactions between proteins that are necessary for biological function, has been extremely challenging, both experimentally and computationally. However, using cryoelectron microscopy to study proteins and macromolecular complexes is one of the highlights of the CNIO structural biology project, which is revolutionizing the way we see and understand how proteins work, as noted a few months ago in the journal Nature.
A comprehensive understanding of the processes that determine how macromolecular complexes are constructed could lead to the discovery of novel cancer treatment strategies based on inhibitory protein assembly. Several studies have shown that inhibiting ruvbl1-ruvbl2 atpase has therapeutic potential in cancer therapy.
The study, published in the journal Science Advances, will help speed up progress in the field, recently conducted by a team led by Llorca of CNIO in collaboration with Laurence h. Pearl of the university of Sussex in the UK.