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New discovery provides insight into complex Rad50 molecular motor function

February 26, 2016

In this study, Tainer and Russell were able to produce crystal and X-ray scattering images of parts of where Rad50 and Mre11 touched each other, and what happened when ATP bound to this complex and what it looked like when it didn't.

In these four new structures, they showed that ATP binding allows Rad50 to drastically change its shape. When not bound to ATP, Rad50 is flexible and floppy, but bound to ATP, Rad50 snaps into a ring that presumably closes around DNA in order to repair it.

"We saw a lot of big movement on a molecular scale," said Tainer. "Rad50 is like a rope that can pull. It appears to be a dynamic system of communicating with other molecules, and so we can now see how flexibly linked proteins can alter their physical states to control outcomes in biology."

"We thought ATP allowed Rad50 to change shape, but now we have proof of it and how it works," Russell said. "This is a key part of the MRN puzzle."

An Engine for Many Vehicles

Rad50 and ATP provide the motor and gas for a number of biological machines that operate across species. These machines are linked to a number of disorders, such as cystic fibrosis, which is caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is a member of the ABC ATPase superfamily.

"Our study suggests that ABC ATPase proteins are used so often in biology because they can flexibly hook up to so many different things and produce a specific biological outcome," Tainer said.

Given this new prototypic understanding of these motors, Tainer and Russell envision a future in which therapies might be designed that target Rad50 when it changes into a shape that promotes a disease. For example, chemotherapy could be coupled with an agent that prevents the MRN complex from repairing DNA damage, promoting death of cancer cells.

"There are some potentially very cool applications to these findings that we are only beginning to think about," Russell said.

Source: Scripps Research Institute