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Structural study reveals clues of cancer-causing protein

Advanced modelling techniques have mapped the structure of a key protein for the development of the nervous system – and cancer, a new study reveals.

Scientists at The Institute of Cancer Research, London, together with colleagues at the London Research Institute, used electron microscopy and X-ray scattering techniques to model the structure of the signalling protein RET, which is key to the development of the central nervous system, and is mutated in several cancer types.

Researchers found that RET bonds with two signalling proteins through four distinct contact sites – in findings that could help in designing new drugs targeting its activity.

The study, published in the journal Cell Reports, was funded by Cancer Research UK.

The RET protein plays a critical role in the development of the central nervous system, while mutated versions have been implicated in cancers such as lung cancer and thyroid cancer.

Previous studies have shown the RET protein has an extracellular domain that spans the cell membrane and projects outside the surface of the cell, allowing it to receive molecular signals that help the cell respond to its environment.

When molecules called growth factors attach to the RET protein, reactions inside the cell are triggered which instruct it to undergo changes, such as dividing or maturing to take on specialised functions.

RET signalling is activated when RET binds with ligand proteins, but only when they also are bound to co-receptors.

Scientists at the ICR used their electron microscopes and their colleagues at the London Research Institute used low-angle X-ray scattering to investigate the structure of a critical RET binding site in human and zebrafish samples.

They found their two methods were able to map the whole of RET’s extracellular domain. In zebrafish, the researchers found that the extracellular domain was shaped like a horseshoe, and that when RET bonded with a key co-receptor it formed a complex consisting of two wings attached to a base.

The researchers used their data to create a 3D model of the complex, showing that the ligand protein is captured beneath its co-receptor, while RET’s extracellular domain wraps around to shield both.

The findings suggest that specific agents targeting regions of RET’s extracellular domain may be able to disrupt RET signalling, which could benefit patients with RET-driven cancer.

Dr Edward Morris, Leader of the ICR’s Structural Electron Microscopy Team, said: “RET deregulation occurs in a range of cancers and drugs which interfere with its kinase activity are already in use to treat thyroid cancer. Researchers have built up RET’s structure in parts but our study brings together multiple techniques to see how the pieces fit together, giving us a complete picture of the system for the first time. New drugs to target the extracellular domain of RET could be of real benefit to patients, so knowing the complete structure of this part of the protein is a really important step.”

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