Protein is an integral part of life. In cells, proteins combine to form large macromolecular complexes that cooperate with each other to perform specific functions. A large number of cancer studies have focused on finding inhibitors of these protein complexes. Kinases such as mTOR and ATR, as well as enzymes such as telomerase, that are overexpressed in tumors, belong to such complexes. The function of some proteins (called chaperones and co-chaperones) is to construct these protein complexes in cells, and inhibition of this assembly process is being studied as an anti-cancer strategy. We can compare kinases and enzymes, such as mTOR, ATR or telomerase, to buildings under construction, and chaperones (such as HSP90) and co-chaperones (such as R2TP) are machines for construction.
Current evidence suggests that targeting RUVBL1-RUVBL2 has the potential to treat cancer. RUVBL1-RUVBL2 is the energy engine that accompanies R2TP. This led the researchers of the DNA damage response team from Spanish National Cancer Research Center (CNIO) to use powerful Cryo-electron microscope to determine the mechanisms that regulate RUVBL1 and RUVBL2. The study was published in the Science Advances.
As mentioned earlier, the team of macromolecular complexes in the DNA damage response determined the high-resolution structure of R2TP using a low temperature electron microscope. In this study, CNIO researchers looked at how cells design R2TP to expose chaperone HSP90 to the proteins it acts on. The R2TP complex has an energy engine and a ring composed of ATP enzyme, RUVBL1 and RUVBL2, which can use the energy released by the hydrolysis of ATP to produce ADP. In this energy production mechanism, ATP enzyme captures ATP in cells and constantly releases ADP as waste and energy.
Image from: Science Advances
Scientists have found that in the ring formed by RUVBL1 and RUVBL2, the pathway of the ATP binding site is completely blocked, and ATP or ADP is stuck in the ring, thus hindering the exchange of energy and the work of the motor. The question is, how to use the energy needed to assemble protein complexes? By looking at the R2TP system under a cryogenic electron microscope, the researchers found the answer. They found a region in RUVBL2 that acts as a channel to control the entry of ATP and ADP into proteins; this process requires the use of energy provided by ATP. The key to adjusting the opening of this door is ATPase RUVBL2 and the R2TP components required for mTOR assembly.
A comprehensive understanding of how macromolecular complexes are constructed will contribute to the discovery of new cancer treatment strategies based on inhibitory protein assembly. Several studies have shown that inhibition of RUVBL1-RUVBL2 ATP enzyme has therapeutic potential in cancer treatment. The recent study, published in the Science Advances, will help accelerate progress in this area.