Scientists Unlock Structure of mTOR, a Key Cancer Cell Signaling Protein

Source: Memorial Sloan Kettering Cancer Center

Summary: Researchers with the help of a cutting-edge research tool called cryo-electron microscopy have solved the structure of an important signaling protein in cancer cells.

When a protein complex called mTOR (rapamycin complex 1) in cells gets triggered, the cells begin to make copies of key ingredients – membranes, DNA and organelles. The cells need these extra ingredients when they want to divvy up and split into daughter cells. Cancer cells too depend on mTOR. In fact, many cancers keep the mTOR protein active essentially all the time to ensure limitless cell division. For many years, scientists have tried to target abnormally active mTOR with drugs as a way to treat cancer, but mTOR-targeted drugs have been disappointing. Researchers from the Memorial Sloan Kettering Cancer Center with the help of a cutting-edge research tool called cryo-electron microscopy (cryo-EM) have solved the structure of mTOR protein complex which may pave the way for rational drug design. The structural study was reported and published in the journal Nature.

mTORC 1 structure revealed with cryo-EM

TOR de force: Using cryo-electron microscopy, researchers have produced this stunningly detailed view of mTORC1, a major signaling hub that is often altered in cancer cells. Credit: MSKCC

The developers of cryo-electron microscopy won the Nobel Prize this year in chemistry. Cryo-EM shoots beams of electrons at proteins which are flash frozen in liquid nitrogen. The electrons bounce off the sample precisely to form an image. The mTOR protein is actually part of several interlocking protein subunits that operate together called the mTORC1 complex. The mTOR enzyme is activated by a protein called RHEB (Ras homologue enriched in brain) and inhibited by one called PRAS40 (Proline-rich Akt substrate of 40 kDa). The newly obtained structure by cryo-EM shows how all these pieces fit together, including how the mTOR enzyme is turned on. Finally, the research team showed how common cancer-associated mutations that occur in this protein effectively keep it in the active state permanently.

Senior research scientist, Dr. Haijuan Yang said, “We figured out that RHEB causes a major conformational change in the complex”, “RHEB binding creates a new interface that doesn’t exist without this binding, then twists the mTOR kinase domain to bring it into the active conformation.”

More Information: Haijuan Yang et al, “Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40”, Nature(2017). DOI: 10.1038/nature25023

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